<p>Research and development programs for adoptive cell therapies continue to expand, but few products make it to late-phase clinical trials, and even fewer receive FDA approval. Despite undergoing extensive validation before entering the trial phase, variable results may be observed in patients due to inherent differences between preclinical models and human subjects as well as heterogeneity between tumors. Moreover, the current clinical evaluation of cell therapies, including CAR-T cells, relies on limited or inconclusive approaches – usually blood sampling or tissue biopsies – lacking spatial and temporal information about their fate in the human body. Here we offer our perspective on how the application of PET imaging to track cell therapies in clinical studies could address these shortcomings and enhance our understanding of cell therapy biodistribution, patients and trial-level therapeutic success or failure, and safety considerations. We further address key challenges, from probe development to methodological, technical, and regulatory, and financial hurdles for integrating PET imaging of cell therapies into clinical studies.</p>