Due to the increasing costs and time consuming for new drug discovery, a large number of pharmaceutical firms have chosen to modify the existing drug molecules for repositioning candidates with new or improved properties, especially those with severe adverse effects, thereby accelerating the drug discovery process. Such strategy has witnessed its success with several examples reported. As the first identified histone lysine specific demethylase, lysine specific demethylase 1 (LSD1) is classified as a member of monoamine oxidase (MAO) superfamily, and specifically removes mono- and dimethylated histone 3 lysine 4 (H3K4) and H3 lysine 9 (H3K9). It has been reported that LSD1 and its downstream targets are involved in cancer cell growth and metastasis. Meanwhile, it is overexpressed in a variety of tumor cells. Inactivating LSD1 specifically inhibits tumor progression and metastasis. Hence, LSD1 inhibition may represent a new and promising direction in anti-cancer drug discovery. Based on the structure and cofactor of LSD1, some clinical applied MAO inhibitors have been identified as LSD1 inactivators. Among them, tranylcypromine presented the most potency against LSD1 and its derivatives were further developed by medicinal chemists in order to develop potent and selective LSD1 inhibitors. Currently, a number of tranylcypromine based LSD1 inhibitors have been developed and two of them, ORY-1001 and GSK2879552, are in clinical trials for cancer treatment. This review highlights recent advances in the repurposing of tranylcypromine and its derivatives as irreversible LSD1 inhibitors for cancer treatment, which are conventionally used for the treatment of depression.