Dendritic cells (DCs) are professional antigen-presenting cells that link innate and adaptive immunity and are critical for the induction of protective immune responses against pathogens. Proportions of these cells are markedly decreased in the blood of untreated HIV-1-infected individuals, suggesting they might be intrinsically involved in HIV-1 pathogenesis. However, despite several decades of active research, the precise role and contribution of these cells to protective or detrimental host responses against HIV-1 are still remarkably unclear. Recent studies have shown that DCs possess a fine-tuned machinery to recognize HIV-1 replication products through a variety of innate pathogen sensing mechanisms, which may be instrumental for generating both cellular and humoral protective immune responses in persons who naturally control HIV-1 replication. Yet, dysregulated and abnormal activation of DCs might also contribute to sustained inflammation and immune activation accelerating disease progression during chronic progressive infection. Emerging data also suggest that DCs can influence the induction of potent broadly-neutralizing antibodies, and may, for this reason, have to be considered as important components of future HIV-1 vaccination strategies. Apart from their involvement in antiviral host immunity, at least a subgroup of DCs seem intrinsically susceptible to HIV-1 infection and may serve as a viral target cell population. Indeed recent studies suggest that specific DC subpopulations residing in the genital mucosa are preferentially infected by HIV-1 and play an active role in sexual transmission; therefore, DCs may contribute to viral dissemination and possible persistence of the viral reservoirs through either direct or indirect mechanisms. Here, we analyze the distinct and partially opposing roles of DCs during HIV-1 disease pathogenesis, with a focus on implications of DC biology natural immune control and HIV cure research efforts.