The introduction of combination antiretroviral therapy (ART) in the 1990s has fundamentally transformed the landscape of HIV medicine, greatly improved disease morbidity and mortality, and reduced transmission rates across all demographic groups. Central to this success was the idea that to achieve best disease outcomes and minimize the development of drug resistance, at least three antiretroviral agents should be used for HIV treatment. This therapeutic strategy is a core tenet of HIV medicine, backed by incontrovertible scientific evidence, and made easy to deploy by the high compliance levels with once-daily coformulations, which have generally been well tolerated. However, there has been increasing support for a paradigm shift toward dual therapy in recent years, particularly during the maintenance therapy phase of treatment. This concept advocates that once virologic suppression has been achieved with at least three antiretroviral drugs during the treatment initiation phase, a switch to a two-drug regimen should be possible. The results of Phase III of the SWORD trials (Llibre et al., Abstract 44LB) and LAMIDOL trial (Joly et al., Abstract 458) presented at the 2017. Conference on Retroviruses and Opportunistic Infections earlier this year seemed to lend support this hypothesis. More new evidence was recently presented at the 2107 International HIV/AIDS Society (IAS) meeting in Paris that adds to the growing body of evidence in favor of a two-drug regimen approach in maintenance therapy. The LATTE-2 study (Eron et al., Abstract 5628) was of major interest because of the exciting new therapeutic options that long-acting injectable antiretroviral agents may bring in the near future. However, more than that, the findings of comparable response between a traditional three-drug oral regimen and a novel injectable two-drug regimen at 96 weeks were quite noteworthy. In this Phase II, multicenter open-label study of 286 HIV-infected ARTnaïve patients, once-daily oral cabotegravir/abacavir/lamivudine achieved virologic suppression in 84% of study participants. In comparison, 87% in the injectable cabotegravir/rilpivirine once every 4-weekly group and 94% in injectable cabotegravir/rilpivirine once every 8-weekly group remained suppressed at 96 weeks. Crucially, no drug resistance mutations were seen in study participants who remained on their regimen. While the idea of a two-drug regimen has been entertained for maintenance therapy, there may be little willingness to push this further into the area of antiretroviral treatment initiation, for the justifiable concerns that exist around the emergence of drug resistance. Despite this, new data presented at the IAS 2017 showed that the idea is not without merit. In a proof of concept, the ACTG A5353 single-arm pilot study of 120 treatment naïve HIV-infected participants with high viral load (VL ≥1000 and >500,000 copies/mL), showed that once-daily dolutegravir/lamivudine had virologic efficacy of 90% at 24 weeks, with 96% of the as-treated study population achieving VL >50 copies/mL (Taiwo et al., Abstract MOAB0107LB). The regimen was well tolerated, with no reported drug resistance mutations while on treatment. There are many real-world advantages to a two-drug regimen approach, among them lower costs (crucial in resource-limited settings where affordability may be a limiting factor), fewer adverse effects or drug toxicities, and possibly improved compliance. These are all important considerations, given that improved mortality now means patients are going to stay on ART treatment for much longer than previously seen. But how the two-drug regimen approach will hold up against firmly held norms and tradition is far from clear, and it is almost certain that the understandable nervousness that surrounds this idea will continue to last. Until the case for the two-drug regimen approach is made more convincingly in ongoing and future trials, the "three or more" rule will reign, not only as the orthodoxy but also as the cornerstone of good clinical practice.