There are three major subfamilies of mitogen-activated protein kinases (MAPK): the extracellular-signal-regulated kinases (ERK MAPK); the c-jun N-terminal kinase or stress-activated protein kinases (JNK or SAPK); and MAPK14. The ERK MAPK pathway is one of the most important for cell proliferation. The MAPK pathways are located downstream of many growth-factor receptors, including that for epidermal growth factor. Overexpression and activation of this receptor are commonly detected in colorectal cancer, and several lines of evidence indicate that overexpression and activation of ERK MAPK play an important part in progression of this cancer. ERK MAPK could be a molecular target for treatment of the disorder. This review focuses on the ERK MAPK signal-transduction pathway, the consequences of its dysregulation in colorectal cancer, and its potential as an approach to cancer treatment. Future challenges for the assessment of these targeted agents in the clinic are also presented.