The use of tramadol, a weak and mixed centrally acting opioid analgesic, has increased steadily over the past decade, a trend influenced by perceived safety advantages over opioid medications such as morphine, oxycodone, and hydrocodone. However, a recent national study reported that older adults account for 33% of tramadol-associated emergency department visits and half of subsequent hospitalizations, suggesting that greater scrutiny of tramadol’s safety in this population is warranted. Tramadol’s adverse effects (e.g., sedation) and the potential for serotonin syndrome and hyponatremia are well recognized by clinicians. However, tramadol-induced seizures and hypoglycemia are particularly harmful to older adults and may further elevate the risk of falls and fractures. The risk of tramadol’s clinically relevant adverse effects is heightened among patients with decreased renal function. By way of brief review, the opioid receptor-mediated analgesic effects are mainly attributed to the active metabolite M1 (O-desmethyltramadol), whereas the inhibition of the neurotransmitter reuptake is caused by the parent drug. The metabolic conversion to the M1 metabolite is mediated primarily through the enzyme CYP2D6, which exhibits substantial genetic variability; consequently, the pharmacologic effect of tramadol is affected by drug-drug and drug-gene interactions. Knowledge of this genetic variability to tramadol’s analgesic response and the potential for drug-drug interactions may help optimize pain control and prevent the emergence of adverse effects.