Patient-centered Explorations in Active Reasoning, Learning, and Synthesis (PEARLS) is a modified instructional method blending characteristics of two classic teaching strategies—problem-based learning (PBL) and case-based learning—with other theory-based and evidence-supported best practices. Several PBL characteristics make it uniquely advantageous for contemporary health profession learners. From the metacognitive and affective dimensions, PBL promotes formation of clinical reasoning, critical thinking, self-assessment, and nontechnical skills (e.g., interpersonal and communication skills, situational awareness). The PEARLS case scenario is the central vehicle through which the learners receive cues informing and guiding their exploration. Substantial resource allocation is required for PEARLS implementation. The four major resource categories include educators, learners, learning environment, and curriculum. The most important limitations to successful PEARLS implementation, however, are curricular. PEARLS learners require sufficient self-directed time for independent research, assimilation, synthesis, and trigger development. Curricula must accommodate the significant workload and time expenditure to promote learner success.