Antiretroviral pre-exposure prophylaxis (PrEP) drugs may be partially effective for preventing HIV transmission. In anticipation of clinical trial results, behavioral HIV prevention scientists have begun examining possible challenges in the implementation of PrEP in clinical practice or community settings. These efforts have acknowledged the need to supplement PrEP drug delivery with risk-reduction counseling and ongoing HIV testing, and we suggest that an even wider range of clinical, diagnostic, behavioral, and monitoring services will be necessary to support PrEP as a population-level HIV prevention strategy. This Commentary offers an integrated structure for optimizing PrEP delivery in clinical practice, which includes five components: 1) PrEP drugs; 2) safety screening and repeated HIV testing; 3) behavioral interventions to facilitate PrEP initiation, maintain adherence, and minimize risk compensation; 4) the development of strategies to engage PrEP users and the healthcare system over the long term; and 5) population-level monitoring. We provide a brief overview of each component and highlight implications of this five-part package for implementation. Attempts to plan for scale-up without explicitly addressing non-pharmaceutical elements may overlook critical implementation needs, barriers, and facilitators.