Introduction: Antagonist is a chemical substance or drug that has the ability to bind to the cell receptor by the ligand-receptor process, but is not able to trigger a response. Antagonists, pharmacologically, mimic the action of an agonist on the cell. It prevents, however, the attachment and function of the agonist or allows the binding but not the appropriate function by blocking the binding site of the agonist on the cell surface. In the past, antagonist production required much  experimentation, trial and error whereas today, with advances in science and identification of molecular structure and signaling techniques, the possibilities of intelligent designs for antagonists in the shortest time possible have arisen. This process is based on two general viewpoints that include: Drug design based on target that can be a receptor or based on the structure of a small molecule as a drug that can block the signaling. The basic structure of an antagonist changes during drug design and hence there could be an antagonist with high levels of activity and minimal side effects. This review studied the new strategies of designing antagonists for cytokines and hormones (focusing on leptin and growth hormone). Since hormones play multiple roles in different physiological conditions and cytokines act as immune modulators, designing antagonists for them or their receptors can play an important role in the treatment of autoimmune-inflammatory-and neoplastic diseases.