As part of the conditioning process to prepare the patient for the bone marrow transplant, the patient is treated with total marrow irradiation (TMI). The purpose of TMI is to eliminate the underlying disease and to suppress the recipient’s immune systems, thus preventing rejection of new donor stem cells. Designing a treatment plan for TMI poses unique challenges that are not present in other forms of site-specific radiation therapy, for example, head-and-neck and prostate treatments. Specifically, the large site to be treated results in clinical treatments where the patient must be positioned far from the isocenter, as well as often repositioned during treatment, thus increasing uncertainty in delivered dose. Designing TMI treatments with intensity modulated radiation therapy (IMRT) will provide more accurate treatments that can spare healthy tissues while simultaneously delivering the prescribed radiation dose to the bones. To bring the patient closer to isocenter, beam orientation optimization (BOO) will be used to incorporate non-coplanar beams. This work will present and discuss in detail the difficulties presented by TMI treatment planning in conjunction with IMRT, as well as the difficulties posed by non-coplanar BOO.