Older adults are using substances, meeting criteria for substance use disorders (SUDs), and experiencing substance-related harm like overdose and death at higher rates than previous generations of older adults. Both the physiological changes of aging and accelerated aging triggered by substance use make older adults and younger adults who use substances uniquely vulnerable to increased harm. Older adults with SUD often develop more complex conditions and life-threatening illnesses. They are seen in emergency rooms, hospitalized, and transferred to post-acute and long-term care facilities at higher rates than any other age group, and these numbers are rising. A whole-person, harm reduction approach is needed to identify and manage the complex biopsychosocial needs of older adults who are facing advanced chronic conditions, age-related disorders, life-limiting illness, and SUD. Both pharmacologic and non-pharmacologic treatment options for older adults with SUDs should consider aging physiology, pharmacokinetics, geriatric syndromes, and socioeconomic and caregiver support. The Geriatric 5Ms (mind, medications, mobility, matters most, and multicomplexity), representing the principles of age-friendly care, is a lens that can be used to reconceptualize SUD care in a holistic framework to improve the care of aging adults who use substances.