Infectious diseases continue to plague the modern world. In the evolutionary arms race of pathogen emergence, the rules of engagement appear to have suddenly changed. Human activities have collided with nature to hasten the emergence of more potent pathogens from natural microbial populations. This is evident in recent infectious disease outbreaks, the events that led to their origin, and lessons learned: influenza (2009), meningitis (Africa, 2009), cholera (Haiti, 2010), E. coli (Germany, 2011) and Salmonella (USA, 2012). Developing a comprehensive control plan requires an understanding of the genetics, epidemiology and evolution of emergent pathogens for which humans have little or no pre-existing immunity. As we plot our next move, nature's genetic lottery continues, providing the fuel to transform the most unlikely infectious disease scenarios into reality.