Alternative pre‐mRNA splicing leads to distinct products of gene expression in development and disease. Antagonistic splice variants of genes involved in differentiation, apoptosis, invasion and metastasis often exist in a delicate equilibrium that is found to be perturbed in tumours. In several recent examples, splice variants that are overexpressed in cancer are expressed as hyper‐oncogenic proteins, which often correlate with poor prognosis, thus suggesting improved diagnosis and follow up treatment. Global gene expression technologies are just beginning to decipher the interplay between alternatively spliced isoforms and protein‐splicing factors that will lead to identification of the mutations in these trans‐acting factors responsible for pathogenic alternative splicing in cancer. BioEssays 28: 378–386, 2006. © 2006 Wiley Periodicals, Inc.