Colorectal cancer (CRC) is now the second-leading cause of cancer deaths in the USA. Colorectal cancer progression and metastasis depends on the orchestration of the aberrant signaling pathways that control tumor cell proliferation, survival and migration/invasion. Epidemiological, clinical, and animal studies have demonstrated that prostaglandin-endoperoxide synthase 2 (PTGS2) and epithelial growth factor (EGF) signaling pathways play key roles in promoting colorectal cancer growth and metastasis. In this review, we highlight major advances in our understanding of the roles of PTGS2 and EGF signaling in colorectal cancer.