The development of a safe and effective HIV vaccine remains a challenge. The modest efficacy seen in the RV144 vaccine trial represented an important milestone for the field. Results from all efficacy studies done to date have generated new information, which has advanced the HIV vaccine field in important ways. In this article, we review the translational research insights from the vaccine efficacy trials completed and fully analyzed to date. We also describe the recent advances in the search for broadly neutralizing antibodies and discuss potential approaches to circumvent the challenge posed by the enormous diversity of HIV-1. The experience from the past 5 years highlights the importance of conducting efficacy studies that continue to move us closer toward the goal of a safe, effective, durable, and universal HIV preventive vaccine.