 In complex organisms, cells must work in harmony to produce a functional whole. Together, they form the tissues, organs, and signaling networks that make life possible. Ironically, one important aspect of this cooperation is cell death. Individual cells must sometimes die to benefit the overall organism. Most cell death research, however, has been conducted at the single cell level, focusing on the mechanisms through which cells die, other than the impact cells death has on surrounding tissues and systems. This special issue of cell death and differentiation highlights research that expands the study of cell death to include its functional consequences, such as its effects on tissue homeostasis, adaptive and pathological inflammatory and immune processes, and responses to antimicrobial and cancer treatments. The effects of a cell's death on surrounding tissue depend on how the cell died. Did it commit suicide by executing the organized program form of cell death called apoptosis? Or was it killed by uncontrolled external factors that led to necrosis and its unregulated digestion? Classically, apoptosis has been viewed as beneficial, a form of cell death that does not cause inflammation or activate the immune system. While necrosis has been viewed as the opposite, a harmful inflammatory process that damages nearby tissue and results in the buildup of decomposing debris. But more recent research has demonstrated how grossly oversimplified this view is. Some forms of cancer cell apoptosis trigger the immune system while necrosis fails to do so in certain contexts. Signaling factors are one of the most critical determinants of how surrounding cells and tissues respond to dead and dying cells. Damaged cells influence how their death will affect their surrounding environment by expressing or releasing what are known as cell death-associated molecular pattern molecules, or C-damps. These molecules provide other cells with instructions such as find me or keep away and eat me or don't eat me, which determine how a cell's remains will be cleared and how likely inflammatory and immune reactions are to follow. While dead cells can be seamlessly disposed of without any harmful consequences, insufficient or disrupted clearance of dead and dying cells is characteristic of autoimmune diseases and tumors. Thus, therapies aimed at correcting such deficiencies have the potential for considerable benefit. The problem is that these deficiencies can arise at any stage in the complex process of cell death. Execution of the death pathway, death-associated signaling by the distressed cell, recognition of those signals, clearance of the corpse, or execution of adaptive immune and inflammatory responses. Therefore, an even greater understanding of the process of cell death and its effects is needed. The studies collected in this special issue of cell death and differentiation contribute to this understanding by highlighting the importance of cell death for the health and function of neighboring tissues and the organism as a whole.