A large number of new drugs have been approved over the past 10 years for the treatment of both common and rare gastrointestinal malignancies. Many other agents, however, have failed at a great cost of financial and patient resources. Drug development must identify potentially active compounds and reveal the most effective and least toxic manner and population in which to administer compounds. Pharmaceutical companies must show therapeutic efficacy and achieve regulatory approval as well as success in the marketplace to recoup their investment. It is worth examining successful examples of drug development such as imatinib, delayed but eventually successful agents such as oxaliplatin, as well as failures such as SU-5416, and applying those lessons to current and future drug development.