This study investigated how students' knowledge of a particular domain influences the type of investigative strategy they utilize in an inquiry learning task within that domain. Students with high domain knowledge were assumed to employ a theory-driven strategy, whereas less knowledgeable students were expected to start off in a data-driven mode of inquiry and gradually shift to a theory-driven strategy. Participants were 36 college freshmen who performed a simulation-based inquiry task in a familiar domain and another, isomorphic task, in an unfamiliar domain. Within-subject comparisons of the hypotheses participants generated on both tasks generally confirmed predicted patterns of strategy use. Results further showed that participants performed the familiar task more successfully. Implications for inquiry learning environments are discussed.