Inflammation contributes to all phases of the atherothrombotic process, patients with elevated inflammatory biomarkers such as high-sensitivity C-reactive protein (hsCRP) have increased cardiovascular risk, and recent work directly implicates the interleukin-1 (IL-1) and interleukin-6 (IL-6) pathways in atherogenesis. Yet, it remains unknown whether targeted inhibition of inflammation will reduce cardiovascular event rates. To address directly this fundamental hypothesis, our research group has initiated two large-scale, randomized, placebo-controlled trials using targeted anti-inflammatory agents for the secondary prevention of myocardial infarction. The first trial, the Cardiovascular Inflammation Reduction Trial (CIRT), has been funded by the NHLBI and will evaluate whether low-dose methotrexate (target dose, 20 mg/wk) as compared to placebo will reduce major vascular events among a group of post-myocardial infarction patients with either diabetes or metabolic syndrome, groups known to have high risk on the basis of a persistent pro-inflammatory response. CIRT is based, in part, on observational evidence of reduced vascular event rates among those treated with methotrexate in the setting of rheumatoid arthritis or psoriatic arthritis and on the ability of methotrexate to reduce TNF, IL-6, and CRP levels. The second trial, the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS), will evaluate whether interleukin-1β (IL-1β) inhibition as compared to placebo can reduce rates of recurrent myocardial infarction, stroke, and cardiovascular death among stable coronary artery disease patients who remain at high vascular risk due to persistent elevations of hsCRP (_2 mg/L) despite contemporary secondary prevention strategies. Canakinumab is a human monoclonal antibody that selectively neutralizes IL-1β, a pro-inflammatory cytokine that plays multiple roles in the atherothrombotic process and that undergoes activation by the NLRP3 inflammasome, a process promoted by cholesterol crystals that in turn leads directly to increased production of IL-1 and IL-6. Together, CIRT and CANTOS will enroll more than 25,000 patients worldwide and provide a fundamental test of the inflammatory hypothesis of atherothrombosis.