Certain subsets of lymphoid cells, such as thymocytes or peripheral B cells, undergo apoptosis after treatment with agents which elevate intracellular 3',5' cyclic adenosine monophosphate (cAMP). Investigators have also noted induction of apoptosis of chronic lymphocytic leukemia (CLL) cells following treatment with methylxanthines, a phenomenon that may, at least in part, be due to the activity of these drugs as non-specific phosphodiesterase (PDE) inhibitors. We discuss three general strategies for altering cAMP-mediated signal transduction in lymphoid cells. After a review of what is known about the expression and regulation of PDE families in human lymphoid cells, we focus on the use of isoform-specific PDE inhibitors as potential therapeutic agents in CLL. Our work has suggested that despite the presence of PDE1, PDE3B, PDE4 and PDE7 enzymes in CLL, inhibition of PDE4 results in uniquely potent induction of apoptosis in CLL cells. This effect is relatively specific as comparable treatment of human peripheral blood T cells does not induce apoptosis. Clinical trials utilizing PDE4 inhibitors are indicated in the therapy of CLL patients resistant to standard therapy.