First discovered in 1984, bicelles have been traditionally used for the structural characterization of membrane-associated proteins through nuclear magnetic resonance (NMR). However, interest has been growing over the past decade in their application to drug delivery. Discoidal particles, such as bicelles, have demonstrated a higher degree of cellular uptake in both in vitro and in vivo models compared to spherical particles, such as lipid nanoparticles. Favorable electrostatic interactions allow the cationic bicelles to efficiently load nucleic acids, including siRNA, for drug delivery and to readily dock onto the anionic cell surface for internalization via adsorptive endocytosis. In this chapter, we provide a detailed description of the formulation methods, an overview of the techniques that are employed for the characterization of the siRNA–bicelle complexes, and approaches to optimizing their cellular uptake.