The present invention is based, in part, on our discovery of compositions and methods that can be used to systemically deplete arginine and thereby treat arginine-dependent cancers. Our studies indicate that administering a composition that depletes arginine directly to the patient's small intestine will provide effective treatment for arginine-dependent cancers. Moreover, the methods can be carried out in such a way that various sources of arginine are restricted and side effects are minimized. For example, to deplete arginine, one can not only administer an arginine-depleting enzyme directly to the intestinal lumen but can also inhibit endogenous production of arginine, reduce arginine production by intestinal bacteria and limit arginine intake. To minimize side effects, one can inhibit protein breakdown, which may occur as a compensatory mechanism, provide systemic NO from a nitric oxide donor, provide a pressor peptide, and/or provide prostacycline or an analog thereof.