Imaging biomarkers (IBs) have been proposed in medical literature that exploit images in a quantitative way, going beyond the visual assessment by an imaging physician. These IBs can be used in the diagnosis, prognosis, and response assessment of several pathologies and are very often used for patient management pathways. In this respect, IBs to be used in clinical practice and clinical trials have a requirement to be precise, accurate, and reproducible. Due to limitations in imaging technology, an error can be associated with their value when considering the entire imaging chain, from data acquisition to data reconstruction and subsequent analysis. From this point of view, the use of IBs in clinical trials requires a broadening of the concept of quality assurance and this can be a challenge for the responsible medical physics experts (MPEs). Within this manuscript, we describe the concept of an IB, examine some examples of IBs currently employed in clinical practice/clinical trials and analyze the procedure that should be carried out to achieve better accuracy and reproducibility in their use. We anticipate that this narrative review, written by the components of the EFOMP working group on “the role of the MPEs in clinical trials”-imaging sub-group, can represent a valid reference material for MPEs approaching the subject.