Many phytochemicals, the bioactive nonnutrient compounds found in plant foods, possess biologic effects associated with reduced risk of various diseases such as cancer. Genetic variation in pathways affecting absorption, metabolism, and distribution of phytochemicals is likely to influence exposure at the tissue level, thus modifying disease risk in individuals. Few studies have examined these gene-phytochemical interactions in humans. In this review, we discuss the sources of variation in metabolism and disposition of phytochemicals, and focus on two aspects of phytochemical handling that have received some attention: the impact of intestinal bacteria and genetically polymorphic phase II, conjugating enzymes.