Much infectious disease research focuses on the interaction of microorganisms and drugs in the laboratory, assuming biological activity of inhibiting organism growth in vitro directly translates to improving patient outcomes in the clinic. Yet in vitro testing does not consider the important role of the human immune system in causing and response to disease. Research shows that patient outcomes are still suboptimal even with disease due to organisms that maintain in vitro susceptibility to currently available drugs. Resources and discussions have focused on “antimicrobial resistance” yet the majority of deaths are with susceptible organisms. Studies of new interventions do not address the questions that patients and clinicians in practice ask in order to improve patient outcomes regardless of causative pathogen in patients who would receive the drugs in the real-world setting. Research in infectious diseases should shift to refocus on improving patient outcomes. This would result in changes in the research questions evaluated, the types of patients enrolled, the comparisons made, the interventions studied, the outcomes evaluated, and the types of statistical evaluations used. In turn this would provide patients and clinicians with better evidence for patient care and justify payment for new interventions.