Chaperone-mediated autophagy (CMA) is a selective process where lysosomes degrade specific proteins in the cytosol, involving a degradation tag, a chaperone, and a translocation complex. Recent studies using transgenic mouse models have shown that CMA plays a crucial role in regulating multiple cellular functions, including glucose and lipid metabolism, DNA repair, cellular reprogramming, and stress response. The discovery of CMA, which was initially resistant to the concept of selective degradation, has expanded our understanding of autophagy and its physiological relevance. CMA is mediated by the KFERQ-like motif, which binds to the chaperone HSC70, and the lysosomal receptor LAMP2A. HSC70 is essential for CMA, while LAMP2A is rate-limiting. CMA is regulated by various signaling pathways, including NFAT, RARα, and the TORC2–AKT1–PHLPP1 axis. CMA is involved in protein quality control, starvation response, metabolic regulation, and immune response. Age-related decline in CMA activity contributes to neurodegenerative disorders and cancer, highlighting its importance in maintaining cellular homeostasis.Chaperone-mediated autophagy (CMA) is a selective process where lysosomes degrade specific proteins in the cytosol, involving a degradation tag, a chaperone, and a translocation complex. Recent studies using transgenic mouse models have shown that CMA plays a crucial role in regulating multiple cellular functions, including glucose and lipid metabolism, DNA repair, cellular reprogramming, and stress response. The discovery of CMA, which was initially resistant to the concept of selective degradation, has expanded our understanding of autophagy and its physiological relevance. CMA is mediated by the KFERQ-like motif, which binds to the chaperone HSC70, and the lysosomal receptor LAMP2A. HSC70 is essential for CMA, while LAMP2A is rate-limiting. CMA is regulated by various signaling pathways, including NFAT, RARα, and the TORC2–AKT1–PHLPP1 axis. CMA is involved in protein quality control, starvation response, metabolic regulation, and immune response. Age-related decline in CMA activity contributes to neurodegenerative disorders and cancer, highlighting its importance in maintaining cellular homeostasis.