The possibility that certain microorganisms might be beneficial to human health is highlighted by the numerous consumer products containing probiotic bacteria. Probiotics are typically administered in food that, following entry into the gastro-intestinal tract, results in measurable health-promoting effects. Although there is a growing list of health benefits provided by the consumption of probiotics, their precise mechanisms of action remain largely unknown. Recent molecular- and genomics-based studies are starting to provide insight into the ways probiotic bacteria sense and adapt to the gastro-intestinal tract environment. Complementary approaches using host cell in vitro systems together with animal models and human volunteers are revealing specific intestinal cell responses to probiotics. These studies should ultimately disclose the molecular mechanisms and pinpoint the bacterial and host effector molecules and pathways by which probiotics are able to modulate human health.