Design of multifunctional nanoparticles for multimodal in-vivo imaging and advanced targeting to diseased single cells for massive parallel processing nanomedicine approaches requires careful overall design, including particle shape, and a multilayered approach to match the multi-step targeting required. In addition to thermodynamically driven self-assembly, complex patterns can be produced by micro-palette and 3D printing approaches. Initial core materials can include nanomaterials that simultaneously serve as x-ray contrast agents for CAT scan imaging as well as T1 or T2 contrast agents for MRI imaging. Use of superparamagnetic iron oxide allows for convenient magnetic manipulation during manufacturing re-positioning inside the body as well as single-cell hyperthermia therapies. To permit real-time fluorescence-image-guided surgery, fluorescence molecules can also be included. Advanced cell targeting can be achieved by attaching antibodies, peptides, aptamers, or other targeting molecules to the nanoparticle in a multilayered approach mimicking the multi-step targeting required. Addition of “stealth” molecules (e.g. PEG or chitosan) to the outer surfaces of the nanoparticles can permit greatly enhanced circulation times. Nanoscale imaging of these manufactured, multifunctional nanoparticles can be achieved either directly through superresolution microscopy or indirectly through single nanoparticle zeta-sizing or x-ray correlation microscopy. Since these multifunctional nanoparticles are best analyzed by technologies permitting analysis in aqueous environments, superresolution microscopy is, in most cases, the preferred method. This review paper will discuss the importance of specific design criteria as well as advantages and disadvantages of each approach. The overall design required a system engineering approach to the problem.