Epithelial cells (ECs) cover the surfaces of the body such as skin, airways, or the intestinal tract and provide an important link between the outside environment and the body interior. Leukocytes play a critical role in immunity, as they are the predominant cell population involved in inflammation and the only cells providing adaptive immune response to pathogenic microorganisms. ECs and leukocytes form a complex network, which regulates processes such as host defense, immunity, inflammation, tissue repair, and cancer growth. One of the most critical functions of ECs is to keep up a barrier to the outside and to protect the sensitive immune system from continuous contact with external microorganisms. An appropriate response to wounding or danger involves not only killing of microbes but also regulation of tissue repair and reconstitution of the barrier system. Dysregulated response to damage represents a pathophysiological mechanism, which leads to autoimmunity, chronic inflammatory diseases, and cancer development. The networks described here are involved in virtually all diseases that take place at body surfaces. In this article, we develop a concept of epithelial barrier as a critical regulator of leukocyte function and discuss how host defense processes modulate epithelial homeostasis.