Microbial interactions are increasingly recognized as an integral part of microbial physiology. Cell-cell communication mediated by quorum sensing and metabolite exchange is a formative element of microbial interactions. However, loss-of-function mutations in quorum-sensing components are common across diverse species. Furthermore, quorum sensing is modulated by small molecules and environmental conditions that may be altered in the presence of other microbial species. Recent evidence highlights how strain heterogeneity impacts microbial interactions. There is great potential for microbial interactions to act as selective pressures that influence the emergence of common mutations in quorum-sensing genes across the bacterial and fungal domains.