The major lysosomal proteolytic pathways essential for maintaining proper cellular homeostasis are macroautophagy, chaperone-mediated autophagy (CMA) and microautophagy. What differentiates CMA from the other types of autophagy is the fact that it does not involve vesicle formation; the unique feature of this pathway is the selective targeting of substrate proteins containing a CMA-targeting motif and the direct translocation into the lysosomal lumen, through the aid of chaperones/co-chaperones localized both at the cytosol and the lysosomes. CMA operates at basal conditions in most mammalian cell models analyzed so far, but it is mostly activated in response to stressors, such as trophic deprivation or oxidative stress. The activity of CMA has been shown to decline with age and such decline, correlating with accumulation of damaged/oxidized/aggregated proteins, may contribute to tissue dysfunction and, possibly, neurodegeneration. Herein, we review the recent knowledge regarding the molecular components, regulation and physiology of the CMA pathway, the contribution of impaired CMA activity to poor cellular homeostasis and inefficient response to stress during aging, and discuss the therapeutic opportunities offered by the restoration of CMA-dependent proteolysis in age-associated degenerative diseases.