Expression of the c-myc and ornithine decarboxylase (ODC) genes is elevated early after mitogenic activation of T-lymphocytes, and regulation of the two genes seems to be coupled to transmembrane signaling pathways that are in part different. The evidence is consistent with protein kinase C (PKC) being both necessary and sufficient to induce expression of the ODC gene in response to treatment of T-cells with either the mitogen concanavalin A (Con A) or biologically active phorbol esters. Furthermore, there seems to be no involvement of events dependent on calmodulin (CaM) in the regulation of ODC in these cells. The situation with c-myc is more complex. In contrast to ODC, transcription of this gene is not stimulated by treatment of resting T-cells with phorbol esters alone, but the cells respond to phorbol esters in combination with the calcium ionophore ionomycin. Induction of the c-myc gene by Con A is inhibited by CaM antagonists. These results are consistent with a model in which transcriptional activation of the c-myc gene in resting T-lymphocytes requires two signals, one from PKC and the other involving CaM.