Lactobacilli and bifidobacteria have traditionally been recognized as potential health-promoting microbes in the human gastrointestinal tract, which is clearly reflected by the pre- and probiotic supplements on the market. Bacterial genomics of lactobacilli and bifidobacteria is initiating the identification and validation of specific effector molecules that mediate host health effects. Combined with advanced postgenomic mammalian host response analyses, elucidations of the molecular interactions and mechanisms that underlie the host-health effects observed are beginning to be gathered. These developments should be seen in the complexity of the microbiota-host relationships in the intestine, which through the new metagenomic era has regained momentum and will undoubtedly progress to functional microbiomics and host response analyses within the next decade. Taken together, these developments are anticipated to dramatically alter the scope and impact of the probiotic field, offering tremendous new opportunities with accompanying challenges for research and industrial application.