This study investigated the effect of two instructional strategies, segmented and holistic, on the progression over time of learners' mental models toward that of an expert with the moderator of cognitive flexibility. Sixty-four juniors and seniors in a college metabolism course were randomly assigned to one of the two strategies for instruction on the electron transport chain. The data were analyzed with a repeated measures general linear model. Mental models progressed significantly for both strategies (p less than 0.001), and a significant interaction was found between cognitive flexibility and instructional strategy on mental model progression (p = 0.02). The segmented strategy was superior for learners with higher cognitive flexibility but inferior to the holistic strategy for lower cognitive flexibility learners. Results have important implications for differentiating instruction on the basis of learner characteristics. (Contains 4 tables and 3 figures.)