For decades, it has been believed that the central dogma of Molecular Biology (DNA → mRNA → Protein) was unidirectional, with all the complex cellular processes of an organism being solely due to the structural and catalytic functions of proteins [1]. Currently, it is widely accepted that this biological complexity is derived from the non-coding DNA portion of the genome, which was once thought of as ‘junk DNA’ (non-codifying DNA). Non-coding RNA (ncRNA) is a class of RNAs which has no potential for translation into proteins. The DNA sequence from which a functional ncRNA is transcribed is often called an RNA gene. The number of ncRNAs within the human genome is unknown; however, massive expansion of global transcriptome datasets from genomics consortia have been demonstrating that most of the human genome is transcribed into non-coding RNAs [2,3,4]. According to the Encyclopedia of DNA elements (ENCODE) project, approximately 75% of the human genome is actively transcribed into ncRNAs [2,5], only 2% of which code for known protein-coding genes [5]. Importantly, ncRNAs have been revealed to be functional and to form complex regulatory networks associated with several biological processes. Disruption of key components of these networks leads to deregulated cell function and contributes to human disease states, including cancer [6,7,8].

Glioblastoma is the most aggressive type of brain cancer in adults, accounting for about half of all primary brain tumors [9]. Despite the multimodal treatment procedure, which consists of maximal resection followed by radiotherapy and chemotherapy, the overall survival rate remains only 12–15 months, highlighting the urgent need for more effective targeted therapy [10].

New insights into the molecular subtypes of diffuse gliomas have led to unprecedented discoveries of potential prognostic and predictive markers [11]. The latest classification system announced by the World Health Organization (WHO) [12] combines the classical histomorphological analysis with molecular genetic tests, allowing more precise diagnosis and guidance for therapeutic interventions [13]. Further studies in this direction should provide the basis for the development of novel therapeutic strategies targeting unique molecular signatures for patient-tailored treatment.

Non-coding RNAs have increasingly been described as biomarkers of various human diseases [14,15,16,17,18] and/or suggested as therapeutic targets [19,20,21,22,23]. In this context, the aim of this article is to review the exciting progress towards elucidating the multifunctional facet of ncRNAs, with special focus on glioblastoma-associated miRNAs and lncRNAs. Finally, we also discuss the limitations and obstacles to translate these findings into the clinical practice.