Probiotics are described as “friendly bacteria” that could improve the intestine defense by interacting with the resident microflora. There is a large body of evidence suggesting that consumption of functional food containing probiotics exerts positive effects on human health. Several clinical trials have highlighted the efficiency of probiotics in the prevention and treatment of different gastrointestinal disorders including the prevention of antibiotic associated diarrhea, the remission in patients with inflammatory bowel disease, beneficial effects against Helicobacter pylori infection, positive effects in patients affected by allergies and atopic diseases. The clinical benefits of probiotics use are mainly attributed to their antimicrobial substances production and their positive interactions with the enterocytes to reinforce the intestinal epithelial barrier. Moreover, there is evidence suggesting that probiotics stimulate both specific and non-specific host immune responses. Recently, have been published some experiments performed with the DNA microarray technology which provided a global gene screening of the complex bacteria-host interplay. Nevertheless, the molecular mechanisms by which probiotics enhance the intestinal host defense are still not completely elucidated. Here, we review the experiments and clinical studies to date on the complex mechanisms regulating the communication between probiotics and their hosts.