The annexins are a family of closely related calcium- and membrane-binding proteins expressed in most eukaryotic cell types. Despite their structural and biochemical similarities annexins have diverse functions, in cellular activities that include vesicle trafficking, cell division, apoptosis, calcium signalling, and growth regulation. To date there is no evidence to suggest that any individual member of the annexin family is a disease-causing gene, i.e., a gene that through loss, mutation, translocation or amplification leads to a known human disease. However, there is good evidence that in certain clinical conditions, changes in annexin expression levels or localisation may contribute to the pathological consequences and sequelae of disease. In this way, annexins are indirectly linked to some of the most serious human disease classes including cardiovascular disease and cancer. In this review we consider the roles played by annexins in disease and examine the molecular basis for anomalous annexin behaviour that may contribute to disease pathophysiology.