Immune checkpoint inhibitors (ICI) represent a cornerstone in cancer treatment. However, the peculiarity of immune response, determining distinctive response patterns and toxicity events, challenges the conventional response criteria. Therefore, the effective tumor response and the real clinical benefit cannot be demonstrated adequately. In this context, recent studies using 2-deoxy-2-[18F]fluoro-D-glucose ([18F]) positron emission tomography/computed tomography (PET/CT) have shown promising results for therapeutic monitoring during ICI, although further research is needed to confirm its potentials. In this review, we focus on the latest evidences and challenges regarding the assessment of morphological and metabolic parameters in the evaluation of ICI therapy. We will also discuss a wide range of emerging imaging-based biomarkers for anti-checkpoint therapy as well as their challenges in the clinical practice.