•High ALDH expression in CSCs is associated with a worse prognosis.•ALDH isozyme expression can to some extent be cancer specific.•Rational approach to chemical modulators of ALDH isozymes provides selectivity.•High expression of certain ALDH isozymes provides an opportunity for drug discovery.•An ALDH inhibitor can only be truly effective in combination treatment. Aldehyde dehydrogenases (ALDHs) belong to a superfamily of 19 isozymes that are known to participate in many physiologically important biosynthetic processes including detoxification of specific endogenous and exogenous aldehyde substrates. The high expression levels of an emerging number of ALDHs in various cancer tissues suggest that these enzymes have pivotal roles in cancer cell survival and progression. Mapping out the heterogeneity of tumours and their cancer stem cell (CSC) component will be key to successful design of strategies involving therapeutics that are targeted against specific ALDH isozymes. This review summarises recent progress in ALDH-focused cancer research and discovery of small-molecule-based inhibitors.