The immune system provides defense against foreign agents that are considered harmful for the organism. Inorganic nanomaterials can be recognized by the immune system as antigens, inducing an immune reaction dependent on the patient's immunological anamnesis and from several factors including size, shape, and the chemical nature of the nanoparticles. Furthermore, nanomaterials-driven immunomodulation might be exploited for therapeutic purposes, opening new horizons in oncology and beyond. In this scenario, we present a critical review of the state of the art regarding the preclinical evaluation of the effects of the most promising metals for biomedical applications (gold, silver, and copper) on the immune system. Because exploiting the interactions between the immune system and inorganic nanomaterials may result in a game changer for the management of (non)communicable diseases, within this review we encounter the need to summarize and organize the plethora of sometimes inconsistent information, analyzing the challenges and providing the expected perspectives. The field is still in its infancy, and our work emphasizes that a deep understanding on the influence of the features of metal nanomaterials on the immune system in both cultured cells and animal models is pivotal for the safe translation of nanotherapeutics to the clinical practice.