Recent advancements in understanding the role of both genetics and molecular pathways in the formation and progression of colorectal cancer have allowed the identification of factors that may be targeted for drug discovery. During the past decade, various approaches have been developed to target specific steps or components of these pathways in order to prevent the development and progression of colorectal cancer and to treat this disease. The innovation and optimization of high-throughput screening methods, as well as the recent emphasis from the NIH on translational sciences, have enabled rapid progress in drug discovery in many fields, including colorectal cancer. Here we present a summary of the recent efforts of targeted high-throughput drug discovery directed at pathways affected in colorectal cancer.