Phosphodiesterase 4 (PDE4) hydrolyzes cyclic adenosine monophosphate (cAMP) and plays a vital roles in many biological processes. PDE4 inhibitors have been widely studied as therapeutics for the treatment of various diseases, including asthma, chronic obstructive pulmonary disease (COPD) and psoriasis. Many PDE4 inhibitors have progressed to clinical trials and some have been approved as therapeutic drugs. Although many PDE4 inhibitors have been approved to enter clinical trials, however, the development of PDE4 inhibitors for the treatment of COPD or psoriasis has been hampered by their side effects of emesis. Herein, this review summarizes advances in the development of PDE4 inhibitors over the last ten years, focusing on PDE4 sub-family selectivity, dual target drugs, and therapeutic potential. Hopefully, this review will contribute to the development of novel PDE4 inhibitors as potential drugs.