Hydrogen sulfide (HS) is the third gaseous signaling molecule that plays important roles in cancer biological processes. Recent studies indicate that HS has both pro-cancer and anti-cancer effects. Endogenous HS can exert pro-cancer functions through induction of angiogenesis regulation of mitochondrial bioenergetics, acceleration of cell cycle progression, and anti-apoptosis mechanisms. Thus, the inhibition of the production of HS in cancer cells may be a new cancer treatment strategy. In contrast to the pro-cancer effect of HS, relatively high concentrations of exogenous HS could suppress the growth of cancer cells by inducing uncontrolled intracellular acidification, inducing cell cycle arrest, and promoting apoptosis. Therefore, HS donors and HS-releasing hybrids could be designed and developed as novel anti-cancer drugs. In this review, the production and metabolism of HS in cancer cells are summarized and the role and mechanism of HS in cancer development and progression are further discussed.