The present study examines the effects of forskolin on U937 cell differentiation. We recently reported that dibutyryl cAMP (dbcAMP), but not cAMP-elevating agents such as histamine, promotes U937 cell differentiation. cAMP production elicited by stimulation of histamine H 2 receptors showed a rapid, homologous desensitization, which might explain the dissimilar responses to histamine and dbcAMP. Forskolin induced an increase in cAMP levels in a concentration-dependent manner (EC 5 0 =30 μM) for an extended period of at least 24 h. Forskolin but not histamine (up to 100 μM), also inhibited cell growth in a dose-dependent fashion (EC 5 0 =22 μM). After 3 days of incubation, 75 μM forskolin induced U937 cell differentiation as judged by an increased rate of reduction of nitrobluetetrazolium (mean±S.E.M.: 21.3±6.6% in treated cells vs. 3.2±1.9% in the control group, P<0.001) and an augmented chemotactic response to complement 5a (C5a) (33.2±5.9% in forskolin-treated vs. 0.34±0.12% in control cells, P<0.01). Furthermore, c-Myc levels decreased following forskolin treatment, while the histamine H 2 receptor agonist dimaprit had no effect. We conclude that forskolin induces U937 cell differentiation through a sustained rise in cAMP levels.