The human promyelocytic leukemia cell line HL-60 was induced to differentiate to mature granulocytic cells by dbcAMP or RA. The influence of distinct protein kinases during different stages of this differentiation was studied by the use of H8, staurosporine and genistein as inhibitors of PKA, PKC and PTK respectively. In dbcAMP-mediated differentiation, the PKA activity of uninduced cells is crucial for the induction of differentiation, but therefore its significance drastically declines and a more important role is played by PKC and PTK. In RA-mediated differentiation, the native state of PKA and PKC activities are necessary and of similar importance for induction. However, the differentiation is enhanced when, following induction, the activities of PKA and PTK are normal and the activity of PKC, in contrast, is temporary suppressed. At the phenotypic stage the effect of inhibition of protein kinases on maturation is in the order PTK > PKC > PKA for the dbcAMP-mediated differentiation and PKC > PKA > PTK for the RA-mediated differentiation. The results indicate that protein kinase activities during differentiation are stage specific and this specificity depends on the inducer used.