Stem cell therapies hold great potential for treatment of neurodegenerative diseases. In this setting, the inability to monitor grafted cell dynamics in the central nervous system limits understanding of cell fates underlying therapeutic response, making therapy design and optimization significantly more challenging. To address this limitation, we aim to design, evaluate, and develop new imaging approaches for detection of human stem cells in vivo. Over-expression of the manganese transporter protein DMT1 in human neural progenitor cells (hNPC) significantly increases intracellular accumulation of the T1-shortening agent Mn2+ and the novel positron emitter 52Mn2+. This work addresses three specific hypotheses: (1) hNPC over-expressing DMT1 are suitable for in vivo cellular imaging, (2) in vivo 52Mn PET and manganese-enhanced MRI are applicable for cell tracking in the rat brain, and (3) Mn-based imaging can be used to detect grafted stem cells in vivo. In addition, we apply the techniques and knowledge developed for stem cell tracking to the characterization and initial in vivo testing of a novel cancer-targeted MRI contrast agent, Gd-DO3A-404. The results of this work establish both the potential and limitations of this approach for in vivo cell tracking. In particular, we find that hNPC transiently over-expressing DMT1 are most suitable for in vivo detection following transplantation. Additionally, the methods for quantitative MRI, 52Mn PET, and cancer-targeted contrast-enhanced MRI developed in this work contribute more broadly to the fields of molecular MRI and multi-modality imaging.