An account of 21st century problem-based learning (PBL) in preclinical medical education is provided through a detailed explanation of the overall process, a description of PBL case construction, and a brief consideration of related activities, including case wrap-up sessions and facilitator debriefing meetings. Composition of student PBL groups, the role of the faculty facilitator, and PBL decorum are also explored in this chapter. The implementation of PBL in a new medical school curriculum by rational design is compared to the introduction of PBL into an existing medical school curriculum by retrofit. Advantages and challenges of PBL are enumerated; a brief comparison of PBL with team-based learning (TBL) is also included.