Over past few years, there has been a dramatic increase in studying physiological mechanisms of the activity of various signaling low-molecular molecules that directly or indirectly initiate adaptive changes in the cardiovascular system cells (CVSC) to hypoxia. These molecules include biologically active endogenous gases or gasotransmitters (H{}_2S, NO and CO) that influence on many cellular processes, including mitochondrial biogenesis, oxidative phosphorylation, K{}^{+}/Ca{}^{2+} exchange, contractility of cardiomyocytes (CM) and vascular smooth muscle cells (VSMC) under conditions of oxygen deficiency. The present review focuses on the mechanistic role of the gasotransmitters (NO, H{}_2S, CO) in cardioprotection. The structural components of these mechanisms involve mitochondrial enzyme complexes and redox signal proteins, K{}^{+} and Ca{}^{2+} channels, and mitochondrial permeability transition pore (MPTP) that have been considered as the final molecular targets of mechanisms underlying antioxidant and mild mitochondrial uncoupling effects, preconditioning, vasodilatation and adaptation to hypoxia. In this article, we have reviewed recent findings on the gasotransmitters and proposed a unifying model of mitochondrial mechanisms of cardioprotection.