Gelsolin is a calcium-activated actin filament severing and capping protein found in many cell types and as a secreted form in the plasma of vertebrates. Mutant mice for gelsolin as well as clinical studies have shown that gelsolin is linked to a number of pathological conditions such as inflammation, cancer and amyloidosis. The tight regulation of gelsolin by calcium is crucial for its physiological role and constitutive activation leads to apoptosis. In the following we will give an overview on how gelsolin is regulated by calcium, and which clinical conditions have been linked to lack or misregulation of gelsolin.