Myelodysplastic syndromes (MDS) are a group of acquired hematopoietic stem cell disorders that manifest with progressive bone marrow failure and have a propensity to transform into leukemia. Although an increase in biologic understanding of MDS has led to improved patient risk stratification and prognostication, advances in treatment have lagged behind. While hematopoietic cell transplantation (HCT) is a potentially curative option for some, most affected patients continue to be treated with supportive care or with drugs that offer temporary palliation such as hematopoietic growth factors, DNA hypomethylating agents, or immunomodulatory therapy. For several groups, such as those with intermediate-risk disease as classified by the Revised International Prognostic Scoring System (IPSS-R) or those with higher-risk disease for whom hypomethylating agents have failed, optimal treatment remains uncertain. Inclusion of patient-related factors such as frailty and comorbid conditions into risk assessment can improve prognostication beyond the disease-associated variables included in systems such as the IPSS-R. This article focuses on approaches to assessing and integrating frailty, comorbidities, and quality of life into the treatment of patients with MDS.