The lysosome is a critical organelle for cellular homeostasis, and dysregulation of lysosomal function has been implicated in a wide range of diseases. TFEB and mTORC1 are two master regulators of lysosomal biogenesis and function, with TFEB promoting lysosomal biogenesis and mTORC1 inhibiting it. Under conditions of stress, such as starvation, the lysosome stress response is activated, which leads to dissociation of mTORC1 from the lysosome, dephosphorylation of TFEB, and activation of lysosomal biogenesis and autophagy. Recently, more transcription factors, such as p53, FOXO1, PPAR, Stat3, NFkB, HIF, HSF, and MITF, have been implicated in lysosome stress response, suggesting a more complex regulatory network for lysosomal function.