Chaperone-mediated autophagy (CMA) is a selective lysosomal proteolytic pathway that plays a critical role in maintaining protein homeostasis and cellular functions across tissues. CMA recognizes proteins through a KFERQ-like motif, which is recognized by the chaperone Hsc70 and delivered to the lysosomal receptor LAMP-2A. This process is essential for degrading misfolded or damaged proteins, regulating cellular energetics, and maintaining proteostasis. CMA is involved in various physiological functions and is implicated in the pathogenesis of diseases such as neurodegenerative disorders, cancer, and immune-related conditions. In neurodegenerative diseases like Parkinson's and Alzheimer's, CMA dysfunction contributes to protein aggregation and neuronal damage. For example, in Parkinson's, CMA failure leads to the accumulation of α-synuclein, exacerbating neurodegeneration. In Alzheimer's, CMA dysfunction promotes tau hyperphosphorylation, contributing to neurodegeneration. CMA also plays a role in cancer by regulating cellular metabolism and tumor cell survival. Dysregulated CMA activity can promote oncogenesis by degrading tumor suppressor proteins and supporting tumor growth. CMA is also involved in immune responses, where it regulates T and B cell functions. In aging, CMA activity declines, leading to impaired protein degradation and increased proteotoxicity. CMA dysfunction is also linked to other pathologies, including cardiovascular diseases, metabolic disorders, and inflammatory conditions. This review highlights the importance of CMA in maintaining tissue homeostasis and its role in disease pathogenesis. It emphasizes the need for further research to understand CMA's regulatory mechanisms and its potential as a therapeutic target for various diseases.Chaperone-mediated autophagy (CMA) is a selective lysosomal proteolytic pathway that plays a critical role in maintaining protein homeostasis and cellular functions across tissues. CMA recognizes proteins through a KFERQ-like motif, which is recognized by the chaperone Hsc70 and delivered to the lysosomal receptor LAMP-2A. This process is essential for degrading misfolded or damaged proteins, regulating cellular energetics, and maintaining proteostasis. CMA is involved in various physiological functions and is implicated in the pathogenesis of diseases such as neurodegenerative disorders, cancer, and immune-related conditions. In neurodegenerative diseases like Parkinson's and Alzheimer's, CMA dysfunction contributes to protein aggregation and neuronal damage. For example, in Parkinson's, CMA failure leads to the accumulation of α-synuclein, exacerbating neurodegeneration. In Alzheimer's, CMA dysfunction promotes tau hyperphosphorylation, contributing to neurodegeneration. CMA also plays a role in cancer by regulating cellular metabolism and tumor cell survival. Dysregulated CMA activity can promote oncogenesis by degrading tumor suppressor proteins and supporting tumor growth. CMA is also involved in immune responses, where it regulates T and B cell functions. In aging, CMA activity declines, leading to impaired protein degradation and increased proteotoxicity. CMA dysfunction is also linked to other pathologies, including cardiovascular diseases, metabolic disorders, and inflammatory conditions. This review highlights the importance of CMA in maintaining tissue homeostasis and its role in disease pathogenesis. It emphasizes the need for further research to understand CMA's regulatory mechanisms and its potential as a therapeutic target for various diseases.