Abstract: A_2B adenosine receptor is involved in the control of mast cell degranulation, interleukin-8 synthesis and cell growth. A_2B adenosine receptor antagonists may serve as novel drugs for asthma, Alzheimer’s disease, cystic fibrosis and type-II diabetes. Therefore, seeking for the highly selective A_2B adenosine receptor antagonists has been one of great interest. The molecular basis, structure-activity relationship of selective A_2B adenosine receptor antagonists and their interactions with A_2B adenosine receptor were reviewed.