Leukocyte adhesion and emigration are involved in host defense and phagocytosis and thus serve a beneficial role during the mounting of a well-contained inflammatory response. However, in certain situations, leukocytes may turn against the host and contribute to tissue damage and organ dysfunction. While trying to summarize the current opinion about the mechanisms by which leukocytes contribute to tissue damage, one finds that leukocyte-inflicted tissue damage involves a network of marked complexity, requiring an orchestrated crosstalk between different cell types, mediators, cytotoxic agents, and their respective inhibitors. Now that an abundance of information is available as to where, when, and how leukocytes contribute to tissue damage, one of the key questions remains unsolved: is leukocyte-inflicted tissue damage true damage, or is it rather a crucial step in tissue repair, healing, and scar formation? Future research will have to address this question, thoroughly differentiating between the role of leukocytes in diverse pathophysiological situations, ranging from cigarette smoke-induced pulmonary emphysema and immune-triggered transplant rejection to myocardial and cerebral infarction. Knowledge of how leukocytes damage tissue only shows us the tools; knowledge of why will provide us with the basis for effective therapeutic interventions.