Tenofovir disoproxil fumarate coformulated with emtricitabine (TDF/FTC) was shown to be effective in preventing HIV acquisition when used for pre-exposure prophylaxis (PrEP), but questions have arisen regarding optimal PrEP implementation strategies.A narrative review of literature since 2010 regarding PrEP effectiveness, implementation, and new prevention modalities was undertaken to summarize lessons learned, and to review potential benefits and challenges.Although daily TDF/FTC is safe, well tolerated, and highly effective in preventing HIV transmission, it has been initiated by only 200,000 Americans, and a comparable number of individuals in other countries, meaning that 80%-90% of those at greatest risk globally have not benefitted yet. Barriers to PrEP uptake have included medication and care costs, anticipated side effects, stigma, and unsupportive health care systems. Innovations to increase PrEP uptake and adherence have included engaging nonmedical staff (eg, pharmacists, social workers, and peer navigators), economic assistance programs, and new technologies (eg, text messaging support and dedicated apps). Pericoital PrEP dosing seems to be effective in preventing HIV transmission among men who have sex with men, but has not been evaluated in women. Investigational PrEP approaches include antiretrovirals delivered by injection, implant, vaginal rings, rectal douches, and immunoprophylaxis. Some of these approaches may allow for infrequent dosing, whereas others may be more congruent with patterns of sexual behavior.PrEP has been shown to be safe and effective when used consistently, but new approaches to enhance uptake, adherence, and convenience with less-frequent dosing are under study, suggesting that new models and modalities will evolve to optimize impact.