Nanostructures represent a promising new type of contrast agent for clinical medical imaging modalities, including magnetic resonance imaging, x-ray computed tomography, ultrasound, and nuclear imaging. Currently, most nanostructures are simple, single-purpose imaging agents based on spherical constructs (e.g., liposomes, micelles, nanoemulsions, macromolecules, dendrimers, and solid nanoparticle structures). In the next decade, new clinical imaging nanostructures will be designed as multi-functional constructs, to both amplify imaging signals at disease sites and deliver localized therapy. Proposals for nanostructures to fulfill these new functions will be outlined. New functional nanostructures are expected to develop in five main directions: Modular nanostructures with additive functionality; cooperative nanostructures with synergistic functionality; nanostructures activated by their in vivo environment; nanostructures activated by sources outside the patient; and novel, nonspherical nanostructures and components. The development and clinical translation of next-generation nanostructures will be facilitated by a combination of improved clarity of the in vivo imaging and biological challenges and the requirements to successfully overcome them; development of standardized characterization and validation systems tailored for the preclinical assessment of nanostructure agents; and development of streamlined commercialization strategies and pipelines tailored for nanostructure-based agents for their efficient translation to the clinic.