The phenylamino-pyrimidine (PAP) nucleus has been demonstrated to be useful for the development of new drugs and is present in a wide variety of antiretroviral agents and tyrosine kinase inhibitors (TKIs). This review aims to evaluate the application of PAP derivatives in drugs and other bioactive compounds. It was concluded that PAP derivatives are still worth exploring, as they may provide highly competitive ATP TKI’s with nano/picomolar activity.