Simple Summary Monoclonal gammopathy of clinical significance (MGCS) refers to a recently coined term describing a complex and heterogeneous group of nonmalignant monoclonal gammopathies. These patients are characterized by the presence of a commonly small clone and the occurrence of symptoms that may be associated with the clone or with the monoclonal protein through diverse mechanisms. This is an evolving, challenging, and rapidly changing field. Patients are classified according to the key organ or system involved, with kidneys, skin, nerves, and eyes being the most frequently affected. However, multiorgan involvement may be the most relevant clinical feature at the presentation or during the course. This review delves into the definition, history, differential diagnosis, classification, prognosis, and treatment of this group of entities by analyzing the evidence accumulated to date from a critical perspective. Monoclonal gammopathies of clinical significance (MGCSs) represent a group of diseases featuring the association of a nonmalignant B cells or plasma cells clone, the production of an M-protein, and singularly, the existence of organ damage. They present a current framework that is difficult to approach from a practical clinical perspective. Several points should be addressed in order to move further toward a better understanding. Overall, these entities are only partially included in the international classifications of diseases. Its definition and classification remain ambiguous. Remarkably, its real incidence is unknown, provided that a diagnostic biopsy is mandatory in most cases. In fact, amyloidosis AL is the final diagnosis in a large percentage of patients with renal significance. On the other hand, many of these young entities are syndromes that are based on a dynamic set of diagnostic criteria, challenging a timely diagnosis. Moreover, a specific risk score for progression is lacking. Despite the key role of the clinical laboratory in the diagnosis and prognosis of these patients, information about laboratory biomarkers is limited. Besides, the evidence accumulated for many of these entities is scarce. Hence, national and international registries are stimulated. In particular, IgM MGCS deserves special attention. Until now, therapy is far from being standardized, and it should be planned on a risk and patient-adapted basis. Finally, a comprehensive and coordinated multidisciplinary approach is needed, and specific clinical trials are encouraged.