During the 2009-2010 Influenza A/H1N1 pandemic, disease severity ranged from mild to severe with multiple factors being associated with the severity of illness. An interaction of multiple viral and host factors is responsible for determining disease severity and disease outcome. We review the role of previously reported risk factors as well as novel immunogenetic factors in determining disease severity. The potential mechanisms by which these factors are thought to contribute to the pathogenesis of severe pA/H1N1 infection are discussed.