The 2009 influenza A (H1N1) pandemic highlighted the importance of quality hospital care of the severely ill, yet there is evidence that the impact of the 2009 pandemic was highest in low- and middle-income countries with fewer resources. Recent data indicate that death and suffering from seasonal influenza and severe illness in general are increased in resource-limited settings. However, there are limited clinical data and guidelines for the management of influenza and other severe illness in these settings. Life-saving supportive care through syndromic case management is used successfully in high-resource intensive care units and in global programs such as the Integrated Management of Childhood Illness (IMCI). While there are a variety of challenges to the management of the severely ill in resource-limited settings, several new international initiatives have begun to develop syndromic management strategies for these environments, including the World Health Organization's Integrated Management of Adult and Adolescent Illness Program. These standardized clinical guidelines emphasize syndromic case management and do not require high-resource intensive care units. These efforts must be enhanced by quality clinical research to provide missing evidence and to refine recommendations, which must be carefully integrated into existing healthcare systems. Realizing a sustainable, global impact on death and suffering due to severe influenza and other severe illness necessitates an ongoing and concerted international effort to iteratively generate, implement, and evaluate best-practice management guidelines for use in resource-limited settings.