In cancer pharmacogenetics (the study of how variability in a single or set of known genes influences drug response) and pharmacogenomics (the study of variability on a genome-wide scale), one of the most important fields of research focuses on the fluoropyrimdines (FPs) and, in particular, 5-fluorouracil (5-FU). After over 40 years of use, FPs remain one of the most commonly used cancer chemotherapy agents and their application includes a wide spectrum of cancer types. FPs also continue to be the baseline component for many new regimens with novel molecular-targeted agents that are being rapidly introduced. Hence, it would seem appropriate that pharmacogenetic/genomic models for optimizing cancer patient management would involve indicators of FP response. In this article, the current trends in FP pharmacogenetics and pharmacogenomics are reviewed based on the advances made to date and the challenges faced in realizing their full potential.