Neoadjuvant therapy is widely accepted as the current standard of care for localized rectal cancer. Downstaging of disease has been significantly improved and pathological complete response rates (pCR) which were historically below 10% with preoperative radiation alone, now range from 15% to 30% with preoperative chemo-radiation. While the availability of new chemotherapeutic drugs (Irinotecan, Oxaliplatin, etc.) and molecular targeted agents (Bevacizamab, Cetuximab, etc.) hold a great deal of promise, results of recent studies indicate that the pCR rate with neoadjuvant therapy appears to have plateaued at 20-30%. The use of more intensive multidrug combinations has, however, significantly increased the toxicity of treatment. New paradigms in neoadjuvant therapy are therefore needed to further improve results of treatment. This review presents strategies for neoadjuvant therapy, with the potential to improve pCR rates and also survival of patients.