Abstract <p>The review summarizes the current understanding of nonclassical cannabinoid receptors, their signaling mechanisms, and roles in physiological and pathological processes. Nonclassical receptors (GPR55, GPR18, GPR119, etc.) demonstrate tissue-specific expression, interaction with multiple G proteins, and ligand-dependent activation of signaling pathways. GPR55 is involved in the regulation of pain, angiogenesis, and oncogenesis; GPR18 modulates inflammation and metabolism; and GPR119 is promising for diabetes therapy. Their ability to heterodimerize has been identified, which complicates their pharmacological profile. Nonclassical cannabinoid receptors represent promising targets for the treatment of socially significant diseases (cancer, diabetes, and neurodegeneration). However, their context-dependent activity requires an in-depth study to develop selective drugs.</p>