Chemotherapeutic agents used in colorectal cancer are frequently associated with severe adverse reactions that compromise the efficacy of treatment. Predicting toxicity could enable therapy to be tailored. Genetic variations have been associated with toxicity in patients treated with fluoropyrimidines (5-fluorouracil, capecitabine and tegafur), oxaliplatin, irinotecan and cetuximab. Complexity of treatment and variability in toxicity classifications make it difficult to compare studies. This article analyzes the association between toxicity and polymorphisms in DPYD, TYMS, MTHFR, ABCB1, UGT1A1, ERCC1, ERCC2, XRCC1, GSTT1 and GSTM1. In addition, the state-of-the-art and future perspectives are discussed.