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Uveal melanoma (UM) is by far the most common intra-ocular tumor in adults and derives from melanocytes. Historically, the initial therapeutic attempts to cure UM has been surgical removal of the eye, with clinically relevant consequences in terms of function, cosmesis, and psychological impact on patients. The Collaborative Ocular Melanoma Study (COMS) introduced the first uniform approach to perform interventional radiotherapy (IRT - brachytherapy) procedures in a standardized way which has allowed to confirm the equivalence of IRT with enucleation in terms of overall survival. Since the introduction of this important milestone, several international guidelines have been issued with regard to specific technical and procedural aspects, and it has allowed IRT to become the mainstream treatment worldwide. However, still nowadays, there is a lack of consensus about the main criteria to definitively assess UM response after IRT. We present a collection of paradigmatic cases treated at our institution and then discuss in detail the latest available evidence about radiological and clinical assessment of UM response after IRT.