Although cyst(e)ine is nutritionally a non-essential amino acid, lymphoid cells cannot synthesize it, rendering their growth dependent on uptake of cyst(e)ine from their microenvironment. Accordingly, we previously suggested that the x(c)- plasma membrane cystine transporter provided a target for lymphoid cancer therapy. Its inhibition could lead to cyst(e)ine deficiency in lymphoma cells via reduction of both their cystine uptake and cysteine supply by somatic cells. In this study, using rat Nb2 lymphoma cultures, drugs were screened for growth arrest based on x(c)- inhibition. Sulfasalazine was fortuitously found to be a novel, potent inhibitor of the x(c)- transporter. It showed high rat lymphoma growth-inhibitory and lytic activity in vitro (IC50 = 0.16 mM), based specifically on inhibition of x(c)--mediated cystine uptake, in contrast to its colonic metabolites, sulfapyridine and 5-aminosalicylic acid. Sulfasalazine was even more effective against human non-Hodgkin's lymphoma (DoHH2) cultures. In rats (n = 13), sulfasalazine (i.p.) markedly inhibited growth of well-developed, rapidly growing rat Nb2 lymphoma transplants without apparent side-effects. Reduced, macrophage-mediated supply of cysteine was probably involved. In five rats, 90-100% tumor growth suppression, relative to controls, was obtained. The x(c)- cystine transporter represents a novel target for sulfasalazine-like drugs with high potential for application in therapy of lymphoblastic and other malignancies dependent on extracellular cyst(e)ine.