PAMAM dendrimers are a new class of macromolecular polymers, with a highly branched three-dimensional structure that provides a high degree of surface functionality and versatility. These nanospherical polymers possess exclusive properties which make them potential carriers for drug and gene delivery. PAMAM dendrimers allow the precise control of size, shape and placement of functional groups that is desirable for many life science applications. However, positive charge at the surface renders cytotoxicity to the cationic PAMAM dendrimers, which limits their clinical usefulness. Modification of dendrimer surface groups is one of the methods available in order to reduce the toxicity and improve their biocompatibility. In this review, firstly a brief description is provided about the characteristics and structure of PAMAM dendrimers. Then, various modification routes with the aim of decreasing the cytotoxicity of PAMAM dendrimers are presented and discussed.