No gene exists in isolation. To be useful, a gene must be functionally expressed and its host must be able to deal with any resulting stresses. Most genes have had sufficient time in their current host that the gene and host have co-evolved to minimize deleterious interactions. However, while this type of coexistence might be the rule, the exceptions can be both interesting and extremely consequential. When, for example, a microbe acquires new genetic material through horizontal gene transfer or synthetic biology, genes must function in an environment with which they did not co-evolve. Efficient use of a new ability will require careful integration into the existing metabolic and regulatory networks of the host. The interactions between gene and host, as well as their evolutionary outcomes, will determine whether a microbe can become pathogenic, remediate a polluted site, or produce a biofuel. Understanding these interactions and the strategies by which evolution optimizes them will allow us to better anticipate the emergence of new microbial phenotypes.