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Twenty-five years ago, an aberrant HIV-1 (now classified as HIV-1 group O) was described from a Cameroonian HIV patient living in Belgium. The epicenter of group O was later found to be in Central Africa, overlapping with the geographical location of the central chimpanzees (Pan troglodytes troglodytes) and western gorillas (Gorilla gorilla), the likely original hosts of group O. Although the prevalence of group O has remained low at 1-2% in Cameroon, some European countries (France, Spain, Belgium) with strong colonial ties to Central Africa have reported the highest prevalence out of Africa. The sequence diversity between HIV-1 group O and M strains is huge, reaching 50 and 30% in the envelope and pol, respectively. This diversity has hindered diagnosis, monitoring, and treatment of group O-infected patients. Due to the intrinsic presence of the C181 mutation in group O, more than 60% of the approximately 30,000 individuals that live with this virus are faced with the challenge of drug resistance to some currently used antiretroviral therapies, notably the non-nucleoside reverse transcriptase inhibitors. Despite its susceptibility to most antiretroviral therapies, some group Os show a high variable baseline susceptibility to enfuvirtide (T20) and maraviroc. Group O strains are the least fit among all HIV-1 and -2 and restrict tetherin using their Nef but not Vpu as reported for group M. Although limited follow-up studies indicate that the natural course of group O is similar to that of M, these viruses are dominantly CCR5 tropic even late in infection, suggesting slow disease progression. This review summarizes important findings that marked the discovery, origin, spread, evolution, pathogenesis, and treatment of group O within the last 25 years.