PURPOSE OF REVIEW: Four randomized trials have investigated the combination of clopidogrel plus aspirin for secondary prevention of vascular outcomes in 54 949 patients. Here we argue that attempts to translate the results of these trials into clinical practice have proven frustrating because of the following statistical considerations: differences in study populations and study design make comparisons difficult (comparisons of 'apples and oranges'), incomplete factorial designs prevent proper contrasts (examining 'bits and pieces' of a larger picture), results concern widely different vascular diseases ('puzzling subgroups'), and negative results are easily misinterpreted. RECENT FINDINGS: Between 1996 and 2004 three major randomized trials assessed combinations of aspirin and clopidogrel, finding: Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) in favor of clopidogrel alone versus aspirin alone, Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) in favor of clopidogrel plus aspirin versus aspirin alone, and Management of Atherothombosis with Clopidogrel in High-risk Patients (MATCH) in favor of clopidogrel plus aspirin versus clopidogrel alone. A recently completed fourth trial (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance; CHARISMA) was a 'negative study' comparing aspirin alone to aspirin plus clopidogrel. SUMMARY: Even after four large randomized trials we still do not know the optimal treatment for secondary prevention of stroke. We suggest that subsequent trials should focus on a particular vascular disease and test hypotheses that relate to a specific mechanism. © 2007 Lippincott Williams & Wilkins, Inc.