Goblet cells reside throughout the gastrointestinal (GI) tract and are responsible for the production and preservation of a protective mucus blanket by synthesizing and secreting high molecular weight glycoproteins known as mucins. The concept of the mucus layer functioning as a dynamic protective barrier is suggested by studies showing changes in mucins in inflammatory conditions of the GI tract, by the altered goblet cell response in germ-free animals, and by the enhanced mucus secretion seen in response to infections. The mucin-containing mucus layer coating the GI epithelium is the front line of innate host defense. Mucins are likely to be the first molecules that invading pathogens interact with at the cell surface and thus, can limit binding to other glycoproteins and neutralize the pathogen. This review will focus on what is known about goblet cell response in various GI infections and the regulatory networks that mediate goblet cell function and mucin production in response to intestinal insults. In addition, we describe the current knowledge on the role of mucins in intestinal innate defense. It is the aim of this review to provide the readers with an update on goblet cell biology and current understanding on the role of mucins in host defense in enteric infections.