A number of novel oral chemotherapeutic agents are entering practice or are under development in the United States. Many of these agents display significant clinical activity against colorectal cancer. Many classes of compounds, including fluoropyrimidine analogs, dihydropyrimidine dehydrogenase (DPD) inhibitors, topoisomerase inhibitors, farnesyl transferase inhibitors, and others, are being developed for oral administration. This manuscript describes the progress of clinical development of these agents and also explores the relative merits and challenges of these approaches. Economic issues, patient preference, and patient selection issues surrounding oral chemotherapy for colorectal cancer will also be discussed.