In the current study, two specific glycosaminoglycan lyases, chondroitinase AC and chondroitinase B, were utilized to examine the roles of chondroitin sulfates and dermatan sulfate in tumor metastasis and angiogenesis. Melanoma cells (SK-MEL) or endothelial cells were treated with either medium or chondroitinase enzyme. Chondroitinase AC inhibited melanoma invasion and proliferation as well as endothelial proliferation and angiogenesis. Apoptosis of melanoma and endothelial cells, as measured by the activity of caspase-3, was also increased by chondroitinase AC, but not by chondroitinase B. Chondroitinase B inhibited endothelial and melanoma proliferation and invasion, but to a lesser extent than chondroitinase AC. Neither chondroitinase had a detectable effect on gelatinase secretion by melanoma cells. These results indicate that both chondroitin and dermatan sulfates regulate many cellular activities related to metastasis.