In response to overwhelming external stimuli, cells are forced to die in different ways. By default, cells are prone to apoptosis, a programmed cell death through the activation of the caspase cascade. However, this process would be blocked if one of the proteins involved in executing apoptosis was genetically impaired or chemically inhibited, or if the apoptotic machinery was not properly operated under specific conditions, such as ischemia and microbial infection. To address these issues, the paradigm of programmed cell death needs to be revised; thus, an alternative form of cell death, programmed necrosis (termed necroptosis, through the caspase-independent pathway), which is distinct from apoptosis in many aspects, has recently been adopted. There is much interest in programmed necrosis as it is very closely associated with pathophysiological conditions, such as stroke, heart attack and septic shock. In an effort to identify target molecules of small compounds interfering with the signaling downstream of tumor necrosis factor-α (TNF-α), necrostatin-1 (Nec-1) was first identified to be a selective allosteric inhibitor of the death domain receptor-associated adaptor kinase, receptor interacting protein 1 (RIP1) in vitro. Since then, some novel scaffolds with selective and distinctive activity have been proposed. In this review, the significant advancement and state-of-art direction for the development of small molecules that can control programmed necrosis is discussed. Furthermore, the perspectives on novel strategies harnessing therapeutic targets identified thus far, are also discussed.