In the last several years, the understanding of gastrointestinal (GI) Paneth cells (PCs) during homeostatic and diseased conditions has remarkably expanded. First, PCs occupy a unique and privileged location within the intestinal stem cells (ISCs) niche, where they play a crucial role in regulating ISC function. PCs are derived from Lgr5+ ISCs but, unlike cells of other epithelial lineages, they remain exclusively at the base of the intestinal crypts. In this position, PCs intimately intermingle with its descendent ISCs where they are believed to provide the canonical Wnt signal required to drive self-renewal and differentiation.