Whereas the apoptosis cell death pathway typically enables cells to undergo death in an immunologically silent manner, cell death by necroptosis induces cell lysis and release of cellular constituents known to elicit an immune response. Consequently, the origins of necroptosis likely originated in host defense against pathogens, although recently it has emerged that dysregulation of the pathway underlies many human pathologies. The past decade has seen a rapid advance in our understanding of the molecular mechanisms underlying necroptotic cell death, including the implication of the pseudokinase, mixed lineage kinase domain-like protein (MLKL), as the terminal effector in the pathway. Here, I review our current understanding of how MLKL is activated by the upstream receptor interacting protein kinase (RIPK)3, the proposed mechanism(s) by which MLKL kills cells, and recently described layers of regulation that tune MLKL's killing activity. Copyright © 2020 Cold Spring Harbor Laboratory Press; all rights reserved.