Granzyme A (GrA) and granzyme B (GrB) play key roles in the induction of target cell death induced by cytotoxic lymphocytes. Whilst these roles have been extensively studied, it is becoming apparent that both granzymes also possess extracellular activities. Soluble granzymes are found extracellularly in normal plasma and are elevated in a number of diseases, ranging from viral and bacterial infections to autoimmune diseases. Here, we discuss the current knowledge of extracellular granzyme substrates, inhibitors and functions; and the pathological consequences of extracellular granzymes in disease. In addition, we provide new evidence for the role of glycosaminoglycan-binding sites of granzymes in extracellular matrix remodeling.