The germ theory of disease, mostly based on single causal pathogenesis, has improved life expectancy and changed human life. Distilling general guidelines on a new generation of public health interventions that acknowledge and use ecology and evolution to reduce the burden of disease remains difficult. Interactions are numerous; their consequences vary, depending on the context, making forecasting difficult. “Last-mile” problems are pervasive, with implementation problems keeping medical knowledge from reaching those most in need. Much of the avoidable burden of infectious disease results from lack of access to modern prevention and treatment methods, from the lack of health structures in poor countries. This chapter concerns major causes of death and disability and suggests that if used strategically, this knowledge could alleviate the burden of infectious diseases. Understanding pathogen-pathogen interactions (e.g., gastrointestinal nematodes and malaria, schistosomiasis and malaria and Wolbachia and filariae) may open opportunities for public health gains.