The field of malignant hematology has experienced extraordinary advancements with survival rates nearly doubling for some leukemias, lymphomas, myeloid malignancies and plasma cell dyscrasias in the past few decades. Five-year survival rates for all cancer now push 70%, transitioning many once life-threatening conditions into chronic medical ailments. Paralleling these advancements have been increasing rates of complex hematologic pain syndromes due to complications from hyperproliferation, thrombosis, lymph node compression, and splenomegaly, as well as being induced by advancements in medical and surgical treatments. Chronic pain syndromes are present in up to 60% of patients with malignancy receiving active treatment and up to 33% of patients during survivorship. Many pharmacologic and non-pharmacologic treatment options have proven efficacy in the management of painful malignant hematologic conditions. However, opioids remain a practice cornerstone. Prevention and management of opioid-related complications has received significant national attention over the past decade and emerging data suggests patients with cancer are at equal if not higher risk of opioid-related complications when compared to patients without malignancy. Numerous tools and procedural practice guides are available to help facilitate safe prescribing. The recent development of cancer-specific resources directing algorithmic use of validated pain screening tools, prescription drug monitoring programs, urine drug screens, opioid use disorder risk screening instruments and controlled substance agreements have further strengthened the framework for safe prescribing. Integrating federal and organizational guidelines with known cancer-patient risk factors, this article offers a case-based discussion to review safe opioid prescribing practices in the hematology setting.