Rational microbial-based therapies have the potential to treat a wide range of diseases and promote wellness. However, we remain severely limited in our ability to employ such therapies, as we cannot predict which bacterial strains have the potential to stably colonize an individual. The Lieberman Lab seeks to close this knowledge gap, developing an understanding of how individual species and strains behave in the human microbiome—including the selective pressures they face, niche ranges, survival strategies, and the degree to which they adapt to individual people. A key approach in the lab is the inference of within-person evolution, using cultured isolates to obtain whole-genome information and new computational methods. We infer past migrations within and across body sites, selective pressures faced by bacteria in vivo, and the molecular strategies used to adapt to these pressures. Crucially, these inferences can be performed without longitudinal studies, because bacterial strains diversify within hosts to form co-existing lineages that preserve a record of their natural history within the host. Other favored approaches include high-throughput culturing and experiments, computational tool development, and interrogation of spatial structure. When possible, we focus on the human environment, in order to rapidly translate discoveries from these complex ecosystems.