Purpose of Review <p>The HIV-1 pandemic is characterized by extensive viral genetic diversity, with strains that can be classified into distinct clades or subtypes based on sequence relatedness. Biological differences between subtypes have also been reported. HIV-1 subtype B, predominant in North America and Europe is most studied, but non-B subtypes represent the majority of infections globally and in sub-Saharan Africa, which accounts for more than two-thirds of people living with HIV. Whereas the implications of genetic and biological diversity overall for HIV prevention, treatment and cure strategies are recognized, the impact of clade differences is contested. Here we review how viral and host diversity, including subtype-specific differences may shape HIV pathogenesis, reservoir characteristics and cure strategies, highlighting data from regions where non-B subtypes circulate.</p> Recent Findings <p>Studies from African and global cohorts highlight differences in epidemiological spread and disease progression among HIV-1 subtypes that may be attributed to viral genetic sequence variations and resultant distinct properties in viral replication capacity, immune evasion, interferon resistance, co-receptor usage, latency regulation and reservoir biology.</p> Summary <p>HIV-1 diversity has implications for virus biology, transmission and clinical outcomes. Clade-specific differences therefore warrant consideration in the development and design of prevention, treatment and cure strategies, including diagnostic and monitoring assays. Incorporating multi-clade research and regionally relevant cohorts will advance and accelerate efforts toward a universally applicable HIV cure.</p>