The article reviews the diverse roles of nitrile-containing pharmaceuticals in medicinal chemistry. Over 30 nitrile-containing drugs are prescribed for various medical indications, with over 20 more in clinical development. The nitrile group, a robust and biocompatible functional group, is not easily metabolized and often plays a key role in molecular recognition. The review focuses on the structural and functional aspects of nitriles, particularly their interactions with biological targets. Key findings include: 1. **Carbonyl Bioisostere**: Nitriles function as carbonyl equivalents in non-steroidal inhibitors, mimicking the interactions of progesterone in the progesterone receptor site. 2. **Hydrogen Bonding**: Nitriles often act as hydrogen bond acceptors, interacting with amino acids or water molecules. 3. **Reversible Inhibition**: Amino nitriles are used as reversible inhibitors of dipeptidyl peptidase (DPP IV) for treating diabetes, with the nitrile nitrogen attacking a serine residue. 4. **Structural Similarity**: Nitriles in different drugs share structural similarities, enhancing their binding affinity and selectivity. 5. **Optimization**: Recent advances in molecular recognition, through crystallography, NMR, and modeling, have improved the understanding of nitrile interactions and led to the development of more effective drugs. The review highlights the versatility and importance of nitriles in drug design, emphasizing their potential for future therapeutic applications.The article reviews the diverse roles of nitrile-containing pharmaceuticals in medicinal chemistry. Over 30 nitrile-containing drugs are prescribed for various medical indications, with over 20 more in clinical development. The nitrile group, a robust and biocompatible functional group, is not easily metabolized and often plays a key role in molecular recognition. The review focuses on the structural and functional aspects of nitriles, particularly their interactions with biological targets. Key findings include: 1. **Carbonyl Bioisostere**: Nitriles function as carbonyl equivalents in non-steroidal inhibitors, mimicking the interactions of progesterone in the progesterone receptor site. 2. **Hydrogen Bonding**: Nitriles often act as hydrogen bond acceptors, interacting with amino acids or water molecules. 3. **Reversible Inhibition**: Amino nitriles are used as reversible inhibitors of dipeptidyl peptidase (DPP IV) for treating diabetes, with the nitrile nitrogen attacking a serine residue. 4. **Structural Similarity**: Nitriles in different drugs share structural similarities, enhancing their binding affinity and selectivity. 5. **Optimization**: Recent advances in molecular recognition, through crystallography, NMR, and modeling, have improved the understanding of nitrile interactions and led to the development of more effective drugs. The review highlights the versatility and importance of nitriles in drug design, emphasizing their potential for future therapeutic applications.