Drug hypersensitivity reaction (DHR) is defined as an immunologically mediated response to a pharmacology agent. Some reactions require prior sensitization and some do not. The interactions between different drugs and the immune system occur by different mechanisms leading to variable clinical features. Some reactions are simple and do not alter patient quality of life. Some are life threatening and require immediate recognition and appropriate therapy. Confirming the diagnosis of DHR is often challenging. The environment in the Intensive care units (ICU) is considered high risk place for DHR development as it offers most of the risk factors. In this review, we offer a delicate combined approach that allows an accurate diagnosis of most of the DHRs encountered in the ICU.