The immune system must discriminate between different forms of cell death to effectively eliminate pathogens and promote healing while avoiding responses to self-antigens, which can lead to autoimmunity. The review discusses the mechanisms by which the immune system determines whether cell death is immunogenic, tolerogenic, or 'silent'. It highlights the role of damage-associated molecular patterns (DAMPs) released from dying cells and the importance of the cell type, activation state, stress, and characteristics of dying cells in determining the immune response. The review also explores the induction of immune tolerance by dying cells, emphasizing the role of factors such as the availability of help, location of dying cells, and receptors involved in their recognition and engulfment. The complexity of these mechanisms is discussed, along with the potential implications for cancer biology, infectious disease, tissue injury, and autoimmunity.The immune system must discriminate between different forms of cell death to effectively eliminate pathogens and promote healing while avoiding responses to self-antigens, which can lead to autoimmunity. The review discusses the mechanisms by which the immune system determines whether cell death is immunogenic, tolerogenic, or 'silent'. It highlights the role of damage-associated molecular patterns (DAMPs) released from dying cells and the importance of the cell type, activation state, stress, and characteristics of dying cells in determining the immune response. The review also explores the induction of immune tolerance by dying cells, emphasizing the role of factors such as the availability of help, location of dying cells, and receptors involved in their recognition and engulfment. The complexity of these mechanisms is discussed, along with the potential implications for cancer biology, infectious disease, tissue injury, and autoimmunity.