The International Prognostic Scoring System (IPSS) for primary MDS assigns four MDS risk categories (Low, INT-1, INT-2, High) based on bone marrow myeloblast percentage, specific cytogenetic abnormalities, and number of cytopenias to estimate survival and risk of transformation to AML. Low and INT-1 risk MDS patients have a median survival of 5.7 and 3.3 years, respectively, in the absence of therapy. Advanced MDS patients in IPSS risk groups INT-2 and High fare much less well with median survival of 1.1 and 0.4 years, respectively. INT-2 and High-risk MDS is also associated with a higher risk of transformation to AML. In addition, hematopoietic precursors from patients with advanced MDS more frequently express the multi-drug resistance (MDR1) gene product P-glycoprotein, possibly explaining the low response rates and short duration of responses in this group after conventional induction therapies. A Phase III trial of the P-glycoprotein inhibitor valspodar in combination with mitoxantrone, etoposide and cytarabine in relapsed or refractory AML and high-risk MDS failed to show improved outcomes with P-glycoprotein inhibition. As such, novel therapeutic strategies to overcome the intrinsic resistance to chemotherapy seen in advanced MDS are needed to improve induction chemotherapy as primary therapy and as a bridge to allogeneic hematopoietic cell transplant.