HMGB1 is an endogenous danger signal that can be released into the extracellular milieu during states of cellular stress or damage, and that is also actively produced by innate effectors such as NK cells subsequently involved in promoting adaptive immunity. HMGB1 has a pivotal role during NK-DC cross talk but, in the context of a chronic viral infection such as that induced by HIV-1, it triggers viral replication in DCs and blocks NK-mediated killing of infected DCs, thus contributing to viral persistence. Increased circulating HMGB1 levels are detected in progressive HIV-1-infected individuals and, in combination with microbial products and TLR ligands, it may also contribute to gut inflammation and subsequently increase microbial translocation and chronic immune activation, a hallmark of HIV-1 disease progression. In order to get a better understanding on the role of HMGB1 in HIV disease and to develop interventions aimed at enhancing immunity to HIV-1, several major questions need to be addressed.