Intracellular levels of cyclic nucleotide second messengers are regulated predominantly by the complex superfamily of cyclic nucleotide phosphodiesterase (PDE) enzymes. Recent advances in our understanding of the molecular pharmacology of these enzymes has led to their identification as biologic regulators of certain disease states and the development of isozyme-selective inhibitors as potential therapeutic agents. A large body of in vitro and preclinical data suggests the therapeutic utility of PDE4 inhibitors as potent anti-inflammatory agents. Early clinical trials with selective PDE inhibitors substantiate this approach while highlighting pharmacodynamic and toxicologic pitfalls inherent to the inhibition of specific PDE isozymes. This commentary will review our current understanding of PDE inhibitors as immunomodulatory agents.