The trillions of microorganisms inhabiting human mucosal surfaces participate intricately in local homeostatic processes as well as development and function of the host immune system. These microorganisms, collectively referred to as the "microbiome," play a vital role in modulating the balance between clearance of pathogenic organisms and tolerance of commensal cells, including but not limited to human allografts. Advances in immunology, gnotobiotics, and culture-independent molecular techniques have provided growing insights into the complex relationship between the microbiome and the host, how it is modified by variables such as immunosuppressive and antimicrobial drugs, and its potential impact on posttransplantation outcomes. Here, we provide an overview of fundamental principles, recent discoveries, and clinical implications of this promising field of research.