Problem solving is a highly valued skill in chemistry. Courses within this discipline place a substantial emphasis on problem-solving performance and tend to weigh such performance heavily in assessments of learning. Researchers have dedicated considerable effort investigating individual factors that influence problem-solving performance. The purpose of this study is to inspect the influences of a core set of factors (prior science achievement, knowledge structures, spatial ability, gender, and ethnicity) and their overall contributions to problem solving in organic chemistry using multivariate regression analyses. Results indicate that knowledge structures are a key predictor of problem-solving performance and account for a significant proportion of the variation in students' problem-solving scores. Implications for research and practice in chemistry are discussed.