The adenoma-carcinoma sequence classically illustrates the multistage aetiology of colorectal cancer. Three genes frequently involved are APC, K-Ras, and TP53. This theoretical model suggests that the genetic lesions that drive the stages include changes that cause the inappropriate activity of oncogenic splice factors or splice factor kinases. The result is a significant change in the ratio of splice isoforms that drastically alter APC, TP53, and K-Ras function. Conventional treatments might cause selective pressures that drive further changes in the alternative splicing of key genes, leading to resistance to therapy.