Mucosal surfaces establish an interface with external environments that provide a protective barrier with the capacity to selectively absorb and secrete materials important for homeostasis of the organism. In man, mucosal surfaces such as those in the gastrointestinal tract, respiratory tree and genitourinary system also represent significant barrier to the successful administration of certain pharmaceutical agents and the delivery of newly designed nano-scale therapeutic systems. This review examines morphological, physiological and biochemical aspects of these mucosal barriers and presents currently understood mechanisms used by a variety of virulence factors used by pathogenic bacteria to overcome various aspects of these mucosal barriers. Such information emphasizes the impediments that biologically active materials must overcome for absorption across these mucosal surfaces and provides a template for strategies to overcome these barriers for the successful delivery of nano-scale bioactive materials, also known as nano-medicines.