Heavy chain disorders are rare B-cell disorders and include heavy chain disease, heavy chain deposition disease, and heavy chain amyloidosis. These disorders share the pathognomonic finding of a truncated immunoglobulin heavy chain without an associated light chain in the serum or urine in the case of heavy chain disease or in the tissues in the case of heavy chain deposition disease and heavy chain amyloidosis but are clinically distinct entities. The clinical recognition and systematic approaches to these disorders are challenging because of the rarity of the diseases, lack of consensus on treatment approaches, and minimal data with novel therapy. Herein we present a review of the literature and 5 consecutive cases at a single institution of gamma heavy chain disease and heavy chain deposition disease treated with novel agents including regimens of CRd (cyclophosphamide, lenalidomide, and dexamethasone), CyBorD (cyclophosphamide, bortezomib, and dexamethasone), R-CVP (rituximab, cyclophosphamide, vincristine, and dexamethasone), BR (bendamustine and rituximab), V-EPOCH (bortezomib, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin), and autologous hematopoietic stem cell transplantation.