The phosphodiesterase 4 (PDE4) enzyme plays a crucial role in the central nervous system (CNS). It is extensively expressed in mammalian brain, where it regulates intracellular cyclic adenosine monophosphate (cAMP) levels. Dysregulation of PDE4 and cAMP balance is associated with various neurodegenerative diseases. By inhibiting PDE4 with drugs, cAMP levels can be stabilized, potentially improving symptoms in mental and neurological disorders such as cognition, depression, and Parkinson's disease. Mechanistically, PDE4 inhibitors exert anti-inflammatory and neuroprotective effects by increasing cAMP accumulation and activating protein kinase A (PKA). This chapter will review the relevant neurological disorders that PDE4 has been associated with and review the preclinical and clinical studies.