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In organic chemistry, spatial reasoning is critical for reasoning about spatial relationships in three dimensions and representing spatial information in diagrams. Despite its importance, little is known about the underlying cognitive components of spatial reasoning and the strategies that students employ to solve spatial problems in organic chemistry. Although prior research suggests that individual differences in visual–spatial ability (assumed to measure facility in visual–spatial imagery) predict success on spatial problems in organic chemistry and explain sex differences in organic chemistry achievement, it is unclear whether students rely on visual–spatial imagery while engaged in chemistry problem solving. In the present study, we investigated which strategies students use to solve spatial chemistry problems and the relationships between strategy choice, spatial ability, and sex. To that end, we explored the use of alternative problem-solving strategies, such as algorithms and heuristics, that may obviate the impact of visual–spatial imagery on problem solving. The results indicated that students employ multiple strategies that include heuristics and the construction of external diagrams rather than relying exclusively on imagistic reasoning. Importantly, we observed students’ choice of strategy to be independent of visual–spatial ability, and we observed that women employ strategies differently than men after instruction in the domain.