Neoadjuvant chemoradiotherapy with fluoropyrimidines is an established treatment in the management of locally advanced rectal cancer. There has been a great deal of research into improving patient outcomes by modifying this regimen by the addition of further radiosensitising agents. One of the difficulties in advancing new combination therapies has been lack of consensus on which surrogate measures best reflect clinically important outcomes. Here we review combinations of the cytotoxic, biological and other agents currently under scrutiny to improve clinical outcomes for patients with colorectal cancer. We also discuss advances in biomarkers that may ultimately result in an ability to tailor neoadjuvant chemoradiotherapy regimens to the somatic gene profile of individual patients.