Microorganisms live in a myriad of ecological niches. The human intestine is among the most densely populated environments; here, a multitude of bacteria appear to have co-evolved to impact beneficially upon the health of their human host. The precise molecular mechanisms and signaling pathways employed by commensal bacteria, including those that facilitate colonization and persistence, remain largely unknown despite the perceived positive effects of such host–microbe interactions. In this review we discuss several fascinating relationships between the gastrointestinal tract and commensal bacteria, with particular emphasis on bifidobacteria as a prototypical group of human enteric microorganisms.