The use of targeting ligands to enhance the delivery of liposomal nanoparticles (LNs) has moved slowly toward clinical application. This relative lack of clinical progression is further complicated by the existence of conflicting in vivo results in the literature. In this work, we describe new formulations of LNs that are targeted with an arginine-glycine-aspartic acid-containing peptide, cRGDfK, conjugated to the lipid distearoyl phosphatidylethanolamine (DSPE). These formulations may be able to circumvent some of the challenges encountered during the development of targeted-LNs. Of the constructs studied, a fluorescently labeled peptide-lipid conjugate was incorporated into LNs with high yield and accuracy. It is shown that the resulting targeted-LNs bind to human umbilical vein endothelial cells (HUVECs) with increasing avidity as the amount of peptide displayed on the LN surface increases. We specifically demonstrate the ability of targeted-LNs loaded with doxorubicin and incubated with HUVECs to deliver the drug to the cytosol. The cell does not internalize nontargeted LNs, supporting the notion that the RGD motif is associated with internalization of the targeted LN.