During the last decade, and with increasing intensity, the potential for using reconstituted high-density lipoprotein (rHDL) particles to deliver hydrophobic drugs to impaired cells and tissues has been explored. Here, we evaluate various parameters that should be considered when utilizing discoidal rHDL particles as a drug delivery platform. Key parameters such as preparation basics, pronounced statistical variation in drug incorporation across rHDL particles, effects of lipid composition on HDL/rHDL in vivo and vitro dynamics/particle stability, and pharmacokinetic/safety data from rHDL infusion studies in human subjects will be addressed including the innate receptors and native functions of HDL. The broad but detailed information presented in this work could also be deployed in other rHDL-related research. However, the major aim of this review is to point out factors that have the potential to advance rHDL research toward realizing the 'magic bullet' for lipophilic and hydrophilic drug delivery in various clinical contexts.