Abstract: The cardioprotective effect of chronic hypoxia (CH) is associated with the activation of inducible nitric oxide synthase (iNOS). Reactive oxygen species (ROS) are involved in the development of CH-induced cardiac tolerance to ischemia/reperfusion. The infarct-limiting effect of CH depends on the opening of mitochondrial ATP-sensitive potassium (mitoKATP) channels. Protein kinase C δ and ε isoforms are involved in the cardioprotective effect of adaptation to hypoxia. CH increases the expression of phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), Ca2+/calmodulin-dependent protein kinase II (CaMKII), phosphorylated p38 (p-p38), phosphorylated AMP-activated protein kinase (p-AMPK), as well as hexokinase-1 (HK1) and hexokinase-2 (HK2). ERK1/2 and mitogen-activated protein kinases (MEK1/2) are involved in the cardioprotective effect of adaptation to hypoxia. The role of atrial natriuretic peptide (ANP), erythropoietin, endothelin-1, phosphoinositide 3-kinases (PI3K), protein kinase G (PKG), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (p38 MAPK) in the protective effect of adaptation to hypoxia requires further research.