Infectious disease emergence into humans from animals or the environment occurs primarily due to genetic changes in the microbe through mutation or re-assortment making it either more transmissible or virulent or through a change in the disease "ecosystem". Research into infectious disease emergence can be grouped into different strategic approaches. One strategic approach is to study a specific or model disease system to understand the ecology of an infectious disease and how is transmitted and propagated through the environment and different hosts and then extrapolate that disease system knowledge to related pathogens. The other strategic approach follows the genomics and phylogenetics-tracking how pathogens are evolving and changing at the amino acid level. Here we argue that for understanding complex zoonotic diseases and for the purposes of preventing emergence and re-emergence into humans, that the Return on Investment be considered for the best research strategy.