Necroptosis is a well-known form of caspase-independent cell death. Necroptosis can be triggered by various extrinsic stimuli including death ligands in the presence of receptor-interacting protein kinase 3 (RIPK3), which is a key mediator of necroptosis induction. Our recent studies revealed that an E3 ligase, C-terminus HSC-70 Interacting Protein (CHIP), functions as an inhibitor of necroptosis. CHIP-/- mouse embryonic fibroblast cells showed higher sensitivity to necrotic stimuli than wild-type mouse embryonic fibroblast cells. Deleterious effects of CHIP knockout were retrieved by RIPK3 depletion. We found that CHIP negatively regulates RIPK3 and RIPK1 by ubiquitylation- and lysosome-dependent degradation. In addition, CHIP-/- mice showed postnatal lethality with intestinal defects, which were rescued by crossing with RIPK3-/- mice. These results suggest that CHIP is a negative regulator of RIPK1 and RIPK3, leading to the inhibition of necroptosis.