We are approaching the thirtieth anniversary of the FDA approval of AZT. This was the first therapeutic agent targeting HIV-1, the retrovirus responsible for the Acquired Immunodeficiency Syndrome (AIDS) that was approved. In that time, AIDS has gone from being an “inherently untreatable” infectious agent to one eminently susceptible to a range of therapies. During a five-year period, starting in the mid-1980s, my group at the National Cancer Institute played a unique and foundational role in the discovery and development of the first generation of antiretroviral agents. We initially focused on AZT and related congeners in the dideoxynucleoside family of nucleoside reverse transcriptase inhibitors (NRTIs), taking them from the laboratory to the clinic in response to the pandemic of AIDS, then a terrifying and lethal disease. Starting with AZT, these drugs proved, above all else, that HIV-1 infection is treatable, and such proof provided momentum for new therapies from many sources, directed at a range of viral targets, at a pace that has rarely, if ever, been matched in modern drug development. Antiretroviral therapy has brought about a substantial decrease in the death rate due to HIV-1 infection, changing it from a rapidly lethal disease into a chronic manageable condition, compatible with very long survival. This has special implications within the classic boundaries of public health around the world, but at the same time, in certain regions, may also affect a cycle of economic and civil instability in which HIV-1/AIDS is both cause and consequence. Many challenges remain, including (1) lifelong duration of therapy; (2) implementation of pre-exposure prophylaxis (PrEP); (3) care coordination and case management for viral suppression in substance-using patients; (4) risk of within-couple, condomless sexual activity when the HIV-1 positive partner is on suppressive antiretroviral treatment; (5) cardiometabolic side effects or other toxicities of long-term therapy; (6) emergence of drug-resistance and viral genetic diversity (non-B subtypes); (7) the specter of new cross-species transmissions from established retroviral reservoirs in apes and Old World monkeys; and (8) the continued pace of new HIV-1 infections in many parts of the world. All of these factors make refining and surpassing current therapies, and developing new therapeutic paradigms, essential priorities.