Although lipoprotein-based drug-delivery was proposed as an outstanding platform for diagnostic and therapeutic applications almost 35 years ago, no lipoprotein based formulations have so far reached the clinical trial stage. Due to small size, long residence time in the circulation and targeted delivery of their payload, several lipoprotein–based formulations have shown a strong potential for translation during pre-clinical studies. Our laboratory has developed a unique drug delivery platform, reconstituted high density lipoprotein nanoparticles (rHDL NPs), utilizing the ingredients of native HDL. The rHDL NPs are capable of transporting drugs instead of the natural cholesteryl ester payload in the interior core of the lipoprotein complex. The rHDL formulation has shown the capability of tumor selective drug delivery, via receptor (SR-B1 targeted) mechanism and thus the potential for broad application in cancer chemotherapy. In addition, the rHDL NPs are good candidates for repositioning/reformulating of drugs that might have failed clinical trials due to poor solubility and excessive off target toxicity. During pre-clinical studies, the rHDL drug delivery technology has shown the potential for reducing the side effects of cancer chemotherapy. Findings from proof of concept studies will be presented that support the strategy for translation of the rHDL technology toward commercial and clinical applications.