The primary goal of nanomedicine is to improve clinical outcomes. To this end, targeted nanoparticles are engineered to reduce non-productive distribution while improving diagnostic and therapeutic efficacy. Paradoxically, as this field has matured, the notion of targeting has been minimized to the concept of increasing the affinity of a nanoparticle for its target. This Opinion article outlines a holistic view of nanoparticle targeting, in which the route of administration, molecular characteristics and temporal control of the nanoparticles are potential design variables that must be considered simultaneously. This comprehensive vision for nanoparticle targeting will facilitate the integration of nanomedicines into clinical practice.