It has been about 100 years since the Spanish influenza pandemic of 1918-19 that killed an estimated 50 million individuals globally. While we have made remarkable progress in reducing infection-related mortality, infections still account for 13 to 15 million deaths annually. This estimate is projected to remain unchanged until 2050. We have identified 4 megatrends in infectious diseases and these are "emerging and re-emerging infections", "antimicrobial resistance", "demographic changes" and "technological advances". Understanding these trends and challenges should lead to opportunites for the medical community to reshape the future. Further inroads will also require broad approaches involving surveillance, public health and translating scientific discoveries into disease control efforts.