The complexity underlying a pathologic process does not necessarily require a complex explanation. The biology determining allograft or cancer rejection, autoimmunity or tissue damage during pathogen infections is complex; however, common patterns are emerging that lead to a common final outcome. For instance, tissue destruction occurs with resolution of the pathogenic process (cancer, infection) or tissue damage and organ failure (autoimmunity, allograft rejection). Observations in humans based on transcriptional profiling converge into what we call an ‘immunologic constant of rejection' that characterizes such occurrences. This constant includes the coordinate activation of interferon-stimulated genes (ISGs) and immune effector functions (IEFs). Understanding this final effector pathway may suggest novel strategies for the induction or inhibition of tissue-specific destruction with therapeutic intent in cancer and other immune pathologies.