Despite the approval of Janus kinase inhibitors and novel agents for patients with myelofibrosis (MF), disease-modifying responses remain limited, and hematopoietic stem cell transplantation (HSCT) remains the only potentially curative treatment option. The number of HSCTs for MF continues to increase worldwide, but its inherent therapy-related morbidity and mortality limit its use for many patients. Furthermore, patients with MF often present at an older age, with cytopenia, splenomegaly, and severe bone marrow fibrosis, posing challenges in managing them throughout the HSCT procedure. Although implementation of molecular analyses enabled improved understanding of disease mechanisms and subsequently sparked development of novel drugs with promising activity, prospective trials in the HSCT setting are often lacking, making an evidence-based decision process particularly difficult. To illustrate how we approach patients with MF with respect to HSCT, we present 3 different clinical scenarios to capture relevant aspects that influence our decision making regarding indication for, or against, HSCT. We describe how we perform HSCT according to different risk categories and, furthermore, discuss our up-to-date approach to reduce transplant-related complications. Last, we show how to harness graft-versus-MF effects, particularly in the posttransplant period to achieve the best possible outcomes for patients.