Magnetic particle imaging (MPI) is a powerful new research and diagnostic imaging platform that is designed to image the amount and location of superparamagnetic nanoparticles in biological tissue. Here, we present mathematical modeling results that show how MPI sensitivity and spatial resolution both depend on the size of the nanoparticle core and its other physical properties, and how imaging performance can be effectively optimized through rational core design. Modeling is performed using the properties of magnetite cores, since these are readily produced with a controllable size that facilitates quantitative imaging. Results show that very low detection thresholds (of a few nanograms Fe(3)O(4)) and sub-millimeter spatial resolution are possible with MPI.