Antiretroviral pre-exposure prophylaxis has huge potential for reducing the rates of new HIV infections in at risk populations. Oral and vaginal antiretroviral formulations have been evaluated in multiple Phase 2B/3 effectiveness trials and there is clear evidence that these products work when used. The converse is also true; antiretrovirals do not work when they are not used. As a consequence, long-acting (LA) injectable and implantable antiretroviral formulations are being developed for the prevention of HIV infection. The two lead products are the non-nucleoside reverse transcriptase inhibitor rilpivirine and the integrase inhibitor cabotegravir. It is hoped that the use of LA antiretroviral PrEP will reduce the burden of product adherence associated with the use of oral and topical products and improve the level of HIV prevention associated with this form of PrEP. Although LA products have clear promise for HIV prevention, there are also challenges to consider. There are concerns about the possibility of idiosyncratic adverse events that would be difficult to manage given the irreversible nature of an LA injection. There are additional concerns about the long half life and extended PK ‘tail’ of these products that might lead to periods of subtherapeutic levels of antiretrovirals; infections acquired during this period might be associated with the development of resistance. The purpose of this presentation is to summarize recent preclinical and clinical research in this area of HIV prevention.