Improved understanding of the molecular mechanisms that mediate cancer progression and therapeutic resistance has identified many therapeutic gene targets that regulate apoptosis, proliferation and cell signalling. Antisense oligonucleotides offer one approach to target genes involved in cancer progression, especially those that are not amenable to small-molecule or antibody inhibition. Better chemical modifications of antisense oligonucleotides increase resistance to nuclease digestion, prolong tissue half-lives and improve scheduling. Indeed, recent clinical trials confirm the ability of this class of drugs to significantly suppress target-gene expression. The current status and future directions of several antisense drugs that have potential clinical use in cancer are reviewed.