Mental-rotation ability modestly predicts chemistry achievement. As such, sex differences in mental-rotation ability have been implicated as a causal factor that can explain sex differences in chemistry achievement and degree attainment. Although there is a correlation between mental-rotation ability and chemistry achievement, laboratory and field studies indicate that students do not always use the same strategies on both measures of visuospatial ability and chemistry achievement assessments. Rather, students apply visuospatial strategies in isolation and in combination with analytical heuristics trained in the chemistry classroom. In this paper, sex differences in strategy use on canonical mental-rotation tasks and isomorphic organic chemistry assessment tasks are examined. Study 1 demonstrates that men and women employ both mental rotation and learned heuristics to compare both simple block shapes and molecular representations after classroom instruction. Study 2, however, demonstrates that practice using an analytical algorithm results in higher achievement than practice using mental rotation for both men and women. Given these findings, the reliability of mental-rotation ability as a predictor of sex differences in chemistry achievement is discussed. (Contains 1 table and 4 figures.)