Science curricula and teaching methods vary greatly, depending in part on which facets of science are emphasized, e.g., core disciplinary ideas or science practices and process skills, and perspectives differ considerably on desirable pedagogies. Given the multi-faceted nature of science and the variety of teaching methods found in practice, it is no simple task to determine what teaching approaches might be most effective and for what purposes. Research into relative efficacy faces considerable challenges, with confounding factors, ambiguities, conflations, and lack of controls being threats to validity. We provide a conceptual framework characterizing the many teaching strategies found in practice as being variants of two fundamental contrasting epistemic modes, and we disentangle conflations of terms and confusions of constructs in both teaching practice and research. Instructional units for two science topics were developed in parallel in the alternative epistemic modes, differing in concept learning paths but otherwise equivalent. We conducted a randomized controlled study of the comparative efficacy of the two modes for learning core disciplinary ideas, using operationally defined active-direct and guided-inquiry teaching methods. Five middle school teachers taught each unit in both modes over 4 years of classroom trials in an 8-day summer program for eighth grade students. Student understanding of core ideas was assessed using pre- and post-tests, and learning gains were analyzed by mode, teacher, topic, and trial year. Although routes to concept understanding were very different in the two modes, eventual student learning gains were similar, within statistical variation. Efficacy variations between and within teachers were greater than between modes, indicating the importance of teacher effects on student achievement. Findings suggest that teachers need not be bound to one mode throughout and can flexibly decide on the pedagogical approach for each concept and situation, on several grounds other than efficacy of core content acquisition alone.