KiSS1 and its cognate G-protein-coupled receptor, GPR54, have diverse functions. While KiSS1 and GPR54 have been intensively studied in physiology, their role in cancer is still unclear. In cancer, KiSS1 and GPR54 have been known to suppress metastasis by inhibiting cancer cell motility. However, recent studies suggest that KiSS1 and GPR54 have varied roles even in cancer development and metastasis. Here, we examine recent advances in understanding the roles of KiSS1 and GPR54 in cancer development and metastasis.