β adrenoceptor (βAR) signaling is finely regulated to mediate the sympathetic nervous system control of cardiovascular function. In neonatal cardiac myocytes, β₁AR activates the conventional G_s/cAMP pathway, whereas β₂AR sequentially activates both the G_s and G_i pathways to regulate the myocyte contraction rate. Here, we show that phosphodiesterase 4D (PDE4D) selectively impacts signaling by β₂AR in neonatal cardiac myocytes, while having little or no effect on β₁AR signaling. Although β₂AR activation leads to an increase in cAMP production, the cAMP generated does not have access to the protein kinase A-dependent signaling pathways by which the β₁AR regulates the contraction rate. However, this restricted access is lost in the presence of PDE4 inhibitors or after ablation of PDE4D. These results not only suggest that PDE4D is an integral component of the β₂AR signaling complex, but also underscore the critical role of subcellular cAMP regulation in the complex control of receptor signaling. They also illustrate a mechanism for fine-tuned βAR subtype signaling specificity and intensity in the cardiac system.