Cell culture data have demonstrated that transferrin, the major iron (Fe) transport protein, is a necessary requirement for cellular proliferation. Evidence suggests that transferrin supports proliferation by providing Fe for critical cellular processes including DNA synthesis. Lymphocytes, similar to other cell types, respond to an increased Fe requirement during proliferation by increased synthesis and expression of surface transferrin receptors. Moreover, under transferrin-Fe-deplete conditions, certain lymphocyte lines exhibit other specialized adaptations that allow for sufficient Fe uptake to support cellular proliferation. These other adaptations include specialized transferrin synthesis and utilization of a transferrin-independent Fe uptake pathway. Lymphocyte proliferation is inhibited by agents that interfere with cellular Fe metabolism; these agents include Fe chelators, class 3a metals that bind to transferrin, and antibodies directed against the transferrin receptor. The data presented in this paper, demonstrate that differences in sensitivity to the effects of these agents are influenced by the amount of available transferrin-Fe and differences in the mechanisms that individual lymphocyte cell lines utilize to ensure adequate Fe uptake to support proliferation. These data support the hypothesis that these agents, if used appropriately, will be useful in the treatment of different lymphoproliferative disorders.