This study tested competing theories about the effectiveness of different instructional sequences for learners with different levels of prior knowledge. Across two classroom experiments, undergraduates learned about noncovalent interactions in biochemistry by either receiving explicit instruction before problem-solving (I-PS group) or engaging in problem-solving before explicit instruction (PS-I group). Then all students completed near- and far-transfer tests on the material. In Experiment 1, participants were introductory biology students (n=367), who had relatively low prior knowledge of the topic. Results indicated that the PS-I group significantly outperformed the I-PS group on the near-transfer test, providing support for productive failure. In Experiment 2, participants were biochemistry students (n=138), who had relatively higher prior knowledge of the topic. In contrast to Experiment 1, results indicated that the I-PS group significantly outperformed the PS-I group, providing support for cognitive load theory. Neither experiment showed significant effects of instructional sequences on the far-transfer test. Overall, the findings suggest the effects of instructional sequences on students with different levels of topic-specific prior knowledge may not be as straightforward as existing theories suggest.