Extracellular vesicles (EVs) are membranous lipid assemblies, which carries a variety of cellular cargo including lipids, proteins, nucleic acids, metabolites, and so on [5]. Generally, these EVs are categorized based on their size and the nature of their biogenesis [6]; nevertheless, there is some overlap within this nomenclature leading to some contradiction [7]. As of yet, there are no set rules to fully categorize EVs. As a result, the International Society of Extracellular Vesicles has advocated the generic term “EVs” for the vesicles released from the cell [8]. Nevertheless, broadly speaking, there are two major classes namely microvesicles (MVs) and exosomes. MVs are also known as ectosomes, microparticles, or shedding vesicles, are vesicles having size ranging from ∼100–1000 nm and are formed from the outward budding of the plasma membrane [9,10]; whereas, exosomes are the vesicles ranging from ∼40 to 120 nm and are formed through a complex process that involves inward budding of endosomes [10,11,12]. Since the discovery of EVs, intensive research has been on-going; nevertheless, as of yet the biology of these EVs especially exosomes are not completely understood. It has been envisaged that exosomes are virtually being released from almost every cell type and they basically facilitate transport of various molecular entities, including nucleic acids, proteins, lipids, and metabolites, both locally and systemically [5,13,14,15,16,17]. Research in the frontiers of exosomes are rapidly increasing; basically a PubMed search with the keyword “exosomes” shows more than thousands of literature been published on the subject, highlighting their importance in the present scenario. Accumulating evidences have ascertained their imperative role in the context of cardiovascular physiology and pathology [18,19,20]. The origin and evolutionary perspective of exosomes and their primordial origin remains enigmatic and understanding of its plausible relation with single celled organism also remains relatively obscure. Exosomes which were once thought to be merely associated with the recycling machinery of the cell, playing role in cellular homeostasis, have undergone pragmatic shift in the field of translational medicine. They are released from wide spectrum of cells, including immune cells such as B cells, T cells, dendritic cells and stem cells, and are present in various biological fluids, such as cerebrospinal fluid, serum, saliva, urine, etc. Evidence has shown that exosomes are mechanistically and functionally diverse from its canonical counterpart and are also more heterogeneous, depending upon its origin [21]. Persistent to its endosomal origin, studies have shown the presence of major lipid rafts components consisting of ceramide, cholesterol, sphingomyelin, phosphoglycerides, long and saturated fatty-acyl chains, etc., in the exosomes. Additionally, since exosomes and multivesicular bodies (MVBs) generally originate with the aid of endosomal sorting complex required for transport (ESCRT) pathway, the proteins related to ESCRT are very prevalent and, in fact, many of them, such as HSP70, HSP90, TSG101, Alix, and tetraspanin family proteins, are considered “signature proteins” of exosomes. This, however, does not imply the absence of any other proteins since exosomes can also arise independent of classical ESCRT pathway and also it is to be noted that they act as a carrier for various protein molecules; thus, their protein profile seems to be wide and varied depending on the conditions. Recent studies have highlighted the importance of membrane proteins in the exosomes which can be leveraged to understand their origin, their preferred cellular destination and pathology of diseased state [21]. In addition to lipids and proteins, exosomes also comprise nucleic acid molecules, including mRNA, miRNA, lncRNA, circRNA, etc., as discussed below. A representative figure highlighting the biogenesis of exosomes and the typical structure of exosomes are presented in Figure 1. As a matter of fact, it is in general consensus that once these exosomes are secreted from the parent cell, they interact with the recipient/responder cells through various mechanism including clathrin-mediated endocytosis, lipid-raft mediated, and/or caveolin-mediated endocytosis, receptor-ligand mediated internalization, phagocytosis or micropinocytosis, and/or direct fusion with the plasma membrane. Lately, it has been evident that these pathways are not mutually explicit and plausibly could co-exist for the internalization of a same population of exosomes [10,22]. For example, Isabella et al., 2009 showed exosome uptake by melanoma cells through the plasma membrane fusion [23]. Similarly, another study identified exosome uptake in neurosecretory PC12 through clathrin-mediated endocytosis [24]. Perhaps, through these mechanisms, these exosomal particles modulate the activity of the recipient cells. The mechanism of exosome uptake is shown in classical cellular cargo transport physiology [10,25]. Further, it has been envisaged that the mode and level of internalization of exosomes by different cells varies widely depending on the cell type and environmental conditions. Unfortunately, but not surprisingly, it has been highlighted that the uptake of exosomes is highest in fibroblast cells and least in cardiomyocytes. Nevertheless, the underlying intricacies regulating exosomal targeting/internalization by cardiomyocyte still remains incompletely understood. Interestingly, Eguchi et al., highlighted that stem cell-derived exosomes containing the anti-apoptotic miRNA-214 are up-taken by the cardiac cells through clathrin-mediated endocytosis [26]. With paucity in the literature underlying molecular intricacies in exosomal internalization and interaction in cardiac cells, not much could be ascertained in the present scenario. Albeit certain speculations could be made based on the understanding obtained from reports on exosomes cell interaction with other cell types. It is envisaged that alteration in its profile gives plethora of information in relation to perturbation in the physiological homeostasis of the body. Interestingly, multiple lines of studies have shown that exosomes with their signature molecules plausibly act as an excellent and minimally invasive biomarker for diagnosis and prognosis of various diseases in general and CVDs in particular. To this end, much literature reviews are available highlighting the potential of exosomal signatures molecules as intriguing biomarkers for variety of pathological conditions including CVDs [27,28,29].