In the last decade, the development of new therapeutic agents modulating the activity of the immune system and boosting its response against cancer has revolutionized the landscape in oncology and paved the way for new therapeutic approaches. In this context, the implementation of the immune checkpoint inhibitors (ICI) has made a turning point in the treatment of metastatic solid tumors and relapsed or refractory lymphomas. Thanks to the targeting of specific immune pathways in the tumor microenvironment (TME), immunotherapy has obtained unpreceded response rates, tumor control rates, and survival benefit, leading to a rapid approval by the FDA (Food and Drug Administration) and the EMA (European Medicines Agency) in numerous oncological settings. Parallel to this renowned therapeutic success, clinicians had to face new challenges in patients’ management, mostly due to the peculiar patterns of response documented during immunotherapy, i.e., pseudoprogression, hyperprogression, and dissociated response. Consequently, the classical morphological response criteria used in oncology could not be sufficient anymore and required several adaptations along the way to deal with the imaging challenges offered by immunotherapy. Similar to morphological criteria, metabolic response criteria based on [18F]FDG PET/CT were modified and adapted to the new therapeutic regimens. Recently, joint guidelines between the main international nuclear medicine societies have been published, aiming to optimize PET/CT recommendations in cancer treatment with checkpoint inhibitors. In the present chapter, a comprehensive insight on the role of [18F]FDG PET/CT in this clinical context will be provided covering major indications in solid tumors and lymphomas investigated during the course of immunotherapy.