Influenza viruses continue to be a major global health threat. Severity and clinical outcome of influenza disease is determined by both viral and host factors. Viral factors have long been the subject of intense research and many molecular determinants have been identified. However, research into the host factors that protect or predispose to severe and fatal influenza A virus infections is lagging. The goal of this review is to highlight the recent insights into host determinants of influenza pathogenesis.