Solid–lipid nanoparticles and nanostructured lipid carriers are delivery systems for the delivery of drugs and other bioactives used in diagnosis, therapy, and treatment procedures. These nanocarriers may enhance the solubility and permeability of drugs, increase their bioavailability, and extend the residence time in the body, combining low toxicity with a targeted delivery. Nanostructured lipid carriers are the second generation of lipid nanoparticles differing from solid lipid nanoparticles in their composition matrix. The use of a liquid lipid together with a solid lipid in nanostructured lipid carrier allows it to load a higher amount of drug, enhance drug release properties, and increase its stability. Therefore, a direct comparison between solid lipid nanoparticles and nanostructured lipid carriers is needed. This review aims to describe solid lipid nanoparticles and nanostructured lipid carriers as drug delivery systems, comparing both, while systematically elucidating their production methodologies, physicochemical characterization, and in vitro and in vivo performance. In addition, the toxicity concerns of these systems are focused on.