TFEB is a mammalian transcription factor that binds directly to the CLEAR consensus sequence (5′‐GTCACGTGAC‐3′) present in the regulatory regions of genes inducing autophagosome formation, autophagosome‐lysosome fusion, hydrolase enzyme expression, and lysosomal exocytosis. By modulating these activities, TFEB coordinates on‐demand control over each cell’s degradation pathway. Thus, a nuclear signaling pathway regulates cellular energy metabolism through TFEB. Our growing understanding of the role of TFEB and CLEAR in the promotion of healthy clearance together with in vitro and in vivo preclinical findings in various animal models of disease supports the conclusion that the pharmacological activation of TFEB could clear toxic proteins to treat both rare and common forms of neurodegenerative disease.