Influenza pandemics are complex events that have occurred frequently throughout human history, three during the past century alone. Now the world is facing the first 21st century pandemic, and the comparison among them is essential to identify common epidemiologic patterns, clinical characteristics, and outcomes. The evolution of medicine, including diagnostic and treatment options, the critical care advances, and global responses are new interventions that could modify the general outcome of the pandemic. Learning from past and current events could lead to a plan for prompt and efficient response in future pandemics and may be help us to predict the unpredictable.