In the current paper several lines of evidence are presented to support our hypothesis that exposure of cancer cells to hydrophobic weak base drugs, and consequent sequestration of these drugs in lysosomes, triggers TFEB-associated lysosomal biogenesis: a) treatment of various drug-naïve cancer cells as well as non-malignant cells with hydrophobic weak base drugs that are highly sequestered in lysosomes, results in a dominant translocation of a FLAG-tagged TFEB from the cytoplasm to the nucleus. This evidence concerns the gene TFEB and cancer.