The utilization of targeted nanoparticles as a selective drug delivery system is a powerful tool to increase the amount of active substance reaching the target site. This can increase therapeutic efficacy while reducing adverse drug effects. However, nanoparticles face several challenges: upon injection, the immediate adhesion of plasma proteins may mask targeting ligands, thereby diminishing the target cell selectivity. In addition, opsonization can lead to premature clearance and the widespread presence of receptors or enzymes limits the accuracy of target cell recognition. Nanoparticles may also suffer from endosomal entrapment, and controlled drug release can be hindered by premature burst release or insufficient particle retention at the target site. Various strategies have been developed to address these adverse events, such as the implementation of switchable particle properties, regulating the composition of the formed protein corona, or using click-chemistry based targeting approaches. This has resulted in increasingly complex particle designs, raising the question of whether this development actually improves the therapeutic efficacy in vivo. This review provides an overview of the challenges in targeted drug delivery and explores potential solutions described in the literature. Subsequently, appropriate strategies for the development of nanoparticular drug delivery concepts are discussed.