The skin and mucous membranes serve as the primary line of defense against pathogens by providing both physical and chemical protection. These barriers are essential in preventing the entry and establishment of microbes, thereby maintaining the integrity of the host.

The outer layer of the skin, the epidermis, is a robust barrier comprising layers of closely packed keratinized cells. This dense arrangement prevents microbes from penetrating the body. The periodic shedding of epidermal cells aids in eliminating microbes present on the skin surface. While bacteria rarely infiltrate the intact surface of a healthy epidermis, injuries such as cuts or burns can compromise this barrier, allowing pathogens to invade tissues or circulate in the bloodstream. Additionally, sebaceous glands in the skin secrete sebum, an oily substance that forms a protective film over the skin surface. Sebum possesses antimicrobial properties, such as the unsaturated fatty acids that inhibit the growth of certain pathogenic bacteria and fungi. The skin's acidity, partly due to the secretion of fatty acids, lactic acid, and perspiration, helps flush microbes from the surface of the skin.

Mucous membranes, which line various body cavities such as the respiratory, gastrointestinal, and urogenital tracts, also act as significant immune barriers. These membranes produce mucus, a viscous fluid that entraps microbes and other foreign particles. In the nasal passages, the mucous membrane has hair that filters out airborne microbes and pollutants. In the upper respiratory tract, cilia – microscopic hairlike projections – propel trapped dust and microbes towards the throat, where they are swallowed or expelled from the body through coughing, sneezing, or swallowing.

The body also produces various fluids that help protect the epithelial surfaces. For instance, the lacrimal apparatus of the eyes generates tears that wash away irritants and contain lysozyme, an enzyme capable of breaking down certain bacterial cell walls. This enzyme is also present in saliva, sweat, nasal secretions, and tissue fluids, all of which aid in reducing microbial colonization of their respective areas. Gastric juice, a mixture of hydrochloric acid, enzymes, and mucus, has potent acidity that destroys many bacteria and most bacterial toxins. Their low pH further enhances the antimicrobial efficacy of these fluids. For instance, the acidic environment of sweat and vaginal secretions creates a hostile environment for many bacteria, inhibiting their proliferation and promoting a healthy microbial balance.