Despite recent advances in treatment options, advanced colorectal cancer (ACC) remains a leading cause of cancer death worldwide, and new therapies are needed to improve the grim prognosis of this disease. Drug development in ACC faces the challenges of a constrained pipeline, a paucity of patients enrolled in clinical trials, and an outdated "one drug fits all" model of clinical research. This article discusses potential innovations in clinical trial design--including enrichment strategies, novel patient populations, and the use of randomization in the phase 2 setting--to optimize the testing of new therapies. It concludes with a selection of promising agents and pathways under investigation in ACC.