Cyclic nucleotide phosphodiesterases (PDE) break down cyclic nucleotides such as cAMP and cGMP, reducing the signaling of these important intracellular second messengers. Several unique families of phosphodiesterases exist, and certain families are clinically important modulators of vasodilation. In the current work, we have summarized the body of literature that describes an emerging role for the PDE4 subfamily of phosphodiesterases in malignancy. We have systematically investigated PDE4A, PDE4B, PDE4C, and PDE4D isoforms and found evidence associating them with several cancer types including hematologic malignancies and lung cancers, among others. In this review, we compare the evidence examining the functional role of each PDE4 subtype across malignancies, looking for common signaling themes, signaling pathways, and establishing the case for PDE4 subtypes as a potential therapeutic target for cancer treatment.