In the last decades, NGR-containing peptides have been proved useful for ligand-directed targeted delivery of various chemotherapeutic drugs to tumor vasculature. Aminopeptidase N (APN; CD13) has been demonstrated to be a key binding site for NGR peptides on tumor vasculature. For drug targeting, chemical means have been applied to couple NGR-peptides to small molecule drugs, such as cytokines, antiangiogenic compounds, viral particles, contrast agents, DNA complexes and other biologic response modifiers. Some products have shown impressive results in preclinical animal models, such as NGR-TNF which was currently tested in Phase III trials. In this article we will review the process of NGR-to-isoDGR transition and provide suggestions for the design of the diverse NGR peptide-chemotherapeutics conjugates.