Hypertension is a major risk factor for ischemic heart disease, stroke, and heart failure. Even moderate blood pressure (BP) elevation can have a significant impact on outcomes. Maintaining BP within recommended levels significantly reduces the risk of cardiovascular morbidity and mortality. Yet, more than one-third of people receiving treatment for hypertension in the United States have uncontrolled BP. When faced with a patient whose BP is no longer controlled, clinicians need to develop a differential diagnosis of potential contributing factors. These factors may include BP measurement issues, poor adherence to antihypertensive medications, therapeutic inertia on the part of clinicians, lifestyle changes, secondary causes of hypertension, or ingestion of substances that interfere with BP control. Patients who demonstrate a deterioration in BP control should be questioned about adherence, recent changes to diet and lifestyle, signs and symptoms of secondary causes of hypertension, and use of any concomitant medications or other substances that may be known to increase BP or interfere with antihypertensive therapy. Common substances that can interfere with BP control include nonsteroidal anti-inflammatory drugs (NSAIDs), oral contraceptives, glucocorticoids, antidepressants, decongestants, alcohol, or other stimulants like cocaine and methamphetamines. Because of the high prevalence of both osteoarthritis and hypertension among elderly people, NSAIDs are a common potential factor in this age group. In the face of worsening BP control, clinicians must actively investigate potential contributing factors and appropriately increase or adjust antihypertensive therapy.