The elevated methionine requirement for the growth of tumors, termed methionine dependence, is a potentially highly effective therapeutic target. To attack this target we are developing anti-methionine chemotherapy. In this study of anti-methionine chemotherapy we have observed that the methionine analog ethionine is synergistic with methionine depletion in arresting the growth of the Yoshida sarcoma both in vitro and when transplanted to nude mice. In contrast, ethionine in vitro in a methionine-containing medium is not effective against Yoshida sarcoma cells. Similarly, ethionine administered along with a methionine-containing diet is ineffective against the Yoshida sarcoma growing in nude mice. A methionine-depleted diet alone is only partially effective against tumor growth. The Yoshida sarcoma gave rise to metastases in 75% of the- organs observed in the mice on the methionine-containing diet, and 43 % of the organs in the mice on the methionine-free diet. In striking contrast, no metastases were observed in the ethionine-treated animals on the methionine-free diet. Anti-methionine chemotherapy consisting of dietary methionine depletion and ethionine administration caused an initial weight loss but the animals weight stabilized resulting in no animal deaths. The synergism of ethionine and methionine depletion is markedly similar in vitro and in vivo suggesting the observed efficacy is due to the specific anti-methionine targeting. Thus methionine depletion highly potentiates the anti-tumor and anti-metastatic effectiveness of ethionine suggesting that anti-methionine chemotherapy consisting of methionine depletion as a modulator of methionine analogs holds great promise as a new, tumor-selective therapeutic approach.