The development of personalised therapy and mechanism-targeted agents in oncology mandates the identification of the patient populations most likely to benefit from therapy. This paper discusses the increasing evidence as to the heterogeneity of the group of diseases called colorectal cancer. Differences in the aetiology and epidemiology of proximal and distal cancers are reflected in different clinical behaviour, histopathology, and molecular characteristics of these tumours. This may impact response both to standard cytotoxic therapies and mechanism-targeted agents. This disease heterogeneity leads to challenges in the design of clinical trials to assess novel therapies in the treatment of "colorectal cancer."