Members of the genus Bifidobacterium are gram-positive bacteria that commonly are found in the gastrointestinal tract (GIT) of mammals, including humans. Because of their perceived probiotic properties, they frequently are incorporated as functional ingredients in food products. From probiotic production to storage and GIT delivery, bifidobacteria encounter a plethora of stresses. To cope with these environmental challenges, they need to protect themselves through stress-induced adaptive responses. We have determined the response of B. breve UCC2003 to various stresses (heat, osmotic, and solvent) using transcriptome analysis, DNA-protein interactions, and GusA reporter fusions, and we combined these with results from an in silico analysis. The integration of these results allowed the formulation of a model for an interacting regulatory network for stress response in B. breve UCC2003 where HspR controls the SOS response and the ClgR regulon, which in turn regulates and is regulated by HrcA. This model of an interacting regulatory network is believed to represent the paradigm for stress adaptation in bifidobacteria.