Intracellular cAMP responses to forskolin (which stimulates independently of hormone receptors) and to several hormones were studied in mouse lymphoid cell lines of B- and T-cell origin and in subpopulations of mouse lymphocytes. In the T-cell lines, isoproterenol caused an increase in cAMP amounting at most to 28% of that caused by 100 microM forskolin. In contrast, in the B-cell lines the increase ranged from 50% to over 100%. In 11 of 13 T-cell lines, forskolin at 1 microM concentration potentiated the isoproterenol response five- to tenfold. Forskolin potentiation was also found in thymocytes and peripheral T-cells but not in B-cell lines. The relative increases in intracellular cAMP evoked by isoproterenol, prostaglandin E2 (PGE2) and histamine varied markedly from cell line to cell line. For instance, three lines carrying the T-helper cell marker L3T4 responded only to PGE2 and not to isoproterenol, whereas two cell lines carrying the Ly2 marker gave a higher response to isoproterenol than to PGE2. The results indicate that subsets of lymphocytes respond differently to various hormones and that these differences are maintained in continuous cell lines.