The immune reconstitution inflammatory syndrome (IRIS) is an important clinical complication in HIV-infected patients initiating antiretroviral therapy. This review focuses on the latest literature pertaining to the pathogenesis of IRIS. The clinical manifestations of IRIS are heterogeneous due to the variety of opportunistic infections that are associated with this inflammatory syndrome. However, the disproportionate inflammation is a defining hallmark for which common mechanisms are suspected. Lymphopenia-induced proliferation in the context of systemic immune activation, presence of high antigenic exposure and a wider availability of interleukin-7 contribute to the exacerbated immune response underlying IRIS. Defect in pathogen clearance by phagocytes might favor high pathogen burden, which in turn is thought to activate both innate immune cells and pathogen-specific T cells upon correction of the CD4 T-cell lymphopenia, predisposing to IRIS. This common scenario might be further invigorated by functional impairments among regulatory T cells. Further insight into the cellular mechanisms driving IRIS is urgently needed. Understanding the relative contribution of distinct effector and regulatory T-cell subsets, and innate immune components to IRIS is required to inspire future therapeutic approaches.