Selective internal radiation therapy has emerged as a well-accepted therapeutic for primary and metastatic hepatic malignancies. This therapeutic modality requires the combined efforts of multiple medical disciplines to ensure the safe delivery of yttrium-90 (90Y)-labeled microspheres. The development of this therapy followed decades of clinical research involving tumor vascularity and microsphere development. Today, it is essential that treating physicians have a thorough understanding of hepatic tumor vascularity and 90Y microsphere characteristics before undertaking this complex intervention. This review explores the contributions of early investigators of this therapy, as well as the development, US Food and Drug Administration approval, manufacturing process, and attributes of the 2 commercially available 90Y radiolabeled microsphere device to clarify the key physical differences between the products.