Avian influenza A (H5N1) viruses cause severe disease in humans, characterized by rapidly progressive pneumonia, multiorgan dysfunction, and high mortality. Poor clinical outcome is associated with high viral load in throat specimens and frequent detection of virus in feces and blood. The latter finding indicates the potential of the virus to disseminate in humans, similar to what occurs in mammals and birds, which is supported by evidence in autopsy studies of virus in extrapulmonary tissues such as liver and brain. Beside direct virus-induced tissue damage, an intense inflammatory response to the virus likely contributes to disease pathogenesis. In vitro and animal experiments showed that H5N1 viruses induce cytokine production in macrophages and respiratory epithelium. In accordance, human H5N1 infections are characterized by increased plasma chemokine and cytokine concentrations, the levels of which correlate with pharyngeal virus load and clinical outcome. Although antiviral therapy forms the mainstay of treatment, the impact of oseltamivir on H5N1-associated mortality seems limited so far. Explanations for this include late institution of treatment, suboptimal dosing and drug delivery, and development of drug resistance, the latter of which may not be a rare event. The focus of clinical management should be on preventing virus and immune-mediated damage by early diagnosis and effective antiviral treatment with regimens, preferably parenteral, that minimize the risk of resistance development.