Methods to detect antigen-specific T cells require access to the accessible and relevant anatomical site(s). When studying humans, this means taking samples of peripheral blood, relying on invasive biopsies, or procuring samples after a rapid autopsy. Investigators who study preclinical models of immune responsiveness mostly rely on samples obtained after euthanasia for a comprehensive analysis of the compartment(s) of interest. The ability to track immune responses non-invasively, and to do so not only for bulk T cells, but also for antigen-specific T cells, would be an important addition to the immunologist’s toolbox. We have developed camelid-derived antibody fragments (nanobodies or VHHs) against a number of surface proteins expressed on lymphocytes and myeloid cells. We apply chemo-enzymatic methods to install radioisotopes for positron emission tomography (PET), so that these nanobodies can now function as imaging agents. Their small size ensures that nanobodies have excellent tissue penetration. Also, free nanobodies are rapidly cleared from the circulation. Based on these two traits, radiolabeled nanobodies hit the sweet spot for immuno-PET imaging agents. We show that immuno-PET can track anti-viral and anti-tumor immune responses longitudinally and non-invasively with millimeter spatial resolution. In the setting of an anti-tumor response under checkpoint blockade, immuno-PET may have prognostic value and help identify responders and non-responders to such therapy. In collaboration with the laboratory of Steve Almo (Albert Einstein College of Medicine) we have begun to use derivatives of Class I MHC products in PET isotope-labeled form to detect antigen-specific CD8 T cells in virus-infected and tumor-bearing mice. Finally, based on theirm imaging characteristics we have exploited several nanobodies as building blocks to create mouse CAR T cells. By having CAR T cells secrete nanobodies that modify the tumor microenvironment their anti-tumor activity can be enhanced.