Persistent inflammation is associated with many chronic human conditions and diseases. Classically, vitamin D is recognized as an essential contributor to mineral and bone homeostasis. Emerging evidence demonstrates that vitamin D is involved in inflammatory responses. Vitamin D receptor (VDR) mediates the biologic functions of vitamin D3, the active form of vitamin D. This review focuses on vitamin D3 and VDR in regulating inflammation. The molecular mechanisms of vitamin D/VDR signaling on inflammatory homeostasis are summarized. Recently, vitamin D3-induced autophagy has been reported. Autophagy contributes to antiinflammation and antimicrobial defense. The functions of autophagy overlap remarkably with those of vitamin D/VDR signaling. Emphasis is placed on the regulatory roles of vitamin D3 on autophagy in inflammation and infection. Finally, the potential application of the insights gleaned from these findings to antiinflammation therapies in chronic inflammatory diseases is discussed.