Drug synergy denotes the phenomenon in which two or more pharmacologically active agents, when administered in combination, produce a total therapeutic effect that exceeds the effect predicted from the individual potencies of the constituent drugs under an appropriate non-interaction reference model. The concept is defined operationally through the quantitative comparison of the observed combination response against a predicted additive response: departures in which the observed effect is greater than the predicted effect are classified as synergy, whereas effects lower than predicted are classified as antagonism, with additivity constituting the null condition of no interaction ^[1][2]. Two principal reference models establish the null hypothesis of non-interaction. Bliss independence assumes that the drugs act by independent mechanisms, such that the combined effect is the product of the probabilities of each drug acting alone, and synergy is declared when the observed effect exceeds this multiplicative prediction ^[3]. Loewe additivity assumes that the drugs share a common mechanism, such that a combination of the two is equivalent to a higher dose of a single agent, and synergy is evaluated through the combination index (CI) or the isobologram: a CI less than 1 indicates synergy, a CI equal to 1 indicates additivity, and a CI greater than 1 indicates antagonism ^[4][5]. The Chou–Talalay method, based on the median-effect equation, provides the most widely used formalization of the CI for quantifying synergy across dose–response data ^[5]. A defining mechanistic feature of drug synergy is that it arises from complementary or cooperative actions on distinct targets or pathways—for example, concurrent inhibition of parallel survival signals, enhancement of drug accumulation, or circumvention of resistance mechanisms—rather than from a simple additive increase in concentration ^[1][2]. The term therefore designates the quantitative excess of combination efficacy over model-predicted additivity, together with the reference models, interaction metrics, and mechanistic rationales through which synergistic drug combinations are identified and characterized ^[1][3][4].