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Chemotherapy regimens containing 5-fluorouracil (5-FU) or the oral pro-drug capecitabine are often used to treat colorectal cancer patients. Unfortunately, toxicity resulting from inappropriate dosing occurs in approximately 33% of patients. Currently, select polymorphisms in the dihydropyrimidine dehydrogenase (DPD) gene (DPYD) are used to predict the occurrence of toxicity and to guide dose reductions. As a vital enzyme involved in the metabolism of 5-FU to inactive metabolites, DPD has been the focus of studies related to 5-FU toxicity. However, patients lacking these variants still experience toxic reactions to fluoropyrimidine treatments. Here, we examined variants in 12 genes within the metabolic pathway of 5-FU and capecitabine, and investigated potentially deleterious DPYD polymorphisms that may contribute to toxicity. These genes include various transporters involved in the efflux of toxic fluoropyrimidines, drug target enzymes, and enzymes involved in the catabolism of 5-FU and capecitabine. Using next generation sequencing, 69 colorectal cancer patients had targeted regions sequenced within the 12 genes. Subjects were initially characterized based on DPYD genotypes (those containing the SNPs predicting toxicity, and those without). The cohort lacking the known DPYD variants were subsequently further characterized based on those who experienced adverse reactions (ARs) to therapy and those who did not. CADD, Polyphen, and SIFT in silico prediction tools were used to identify potentially deleterious variants. More predicted deleterious variants were identified exclusively within the AR cohort than the no reaction cohort. We propose several polymorphisms within multiple genes that could have contributed to toxicity seen within both DPYD genotype cohorts. In order to create a more comprehensive screening technique, it is essential to further investigate the role these deleterious variants may have in the toxic build up of fluoropyrimidines within cells. This may help clinicians improve patient care, and result in less ARs to fluoropyrimidine based treatments.