Cyclic nucleotides (e.g., cAMP and cGMP) are ubiquitous second messengers that affect multiple cell functions including vascular tone and vascular cell proliferation. After production, different processes can regulate the concentration of cyclic nucleotides. Cyclic nucleotides' degradation by phosphodiesterase (PDE) enzymes has well-known roles in regulating cyclic nucleotides concentrations. Recently, recognition of ATP-binding cassette (ABC) transporter contribution to both local and global regulation of cAMP has been acknowledged. Recent data support an important role of cyclic nucleotide efflux in the pathobiology of pulmonary hypertension, thus suggesting that inhibition of cyclic nucleotide efflux proteins might be a useful strategy to prevent and treat PH.