Diffusion-weighted MRI (DWI) in combination with perfusion-weighted MRI (PWI) has become a widely accepted modality for the selection of patients amenable for acute therapy, if a mismatch between these procedures suggests viable penumbral tissue. However, DWI as well as PWI yields semiquantitative measures limiting the definitions of irreversible damage and of potentially viable penumbral tissue. These limitations of PWI/DWI may be better understood if findings in individual patients are compared with the results from measurements of blood flow, oxygen metabolism, and benzodiazepine receptor binding obtained with positron emission tomography (PET). Comparative studies with PET and MRI were performed in 3 groups of patients: (1) In 12 acute stroke patients, results from DWI (median, 6.5 hours after symptom onset) and 11C-flumazenil (FMZ) PET (median, 85 minutes between DWI and PET) were compared with infarct extension 24 to 48 hours later on T2-weighted MRI. (2) In 11 acute stroke patients, results from PWI (median, 8 hours after symptom onset) were compared with cerebral blood flow measurements obtained with [15O]H2O PET (interval, 60 minutes between PWI and PET). (3) In 10 patients with acute (n=5) or chronic stroke (n=5), results from PWI/DWI were compared with PET of cerebral blood flow and oxygen consumption to detect mismatch or increased oxygen extraction fraction as surrogate markers of penumbra. Results were: (1) from regions with increased DWI intensity, decreased apparent diffusion coefficient (ADC) and decreased FMZ binding probability curves were computed for eventual infarction, and 95% prediction limits were determined. These limits predicted 83.5% (FMZ), 84.7% (DWI), and 70.9% (ADC) of the final infarct volume. However, the false-positive predictions were much higher for the DWI variables (5.1 and 3.6 cm3 for DWI and ADC versus a median of 0 for FMZ). (2) The comparison of volumes generated by different time to peak (TTP) thresholds (PWI) and hypoperfusion <20 mL/100 g per minute (PET) indicates that a TTP delay of 4 to 6 seconds yields a fair estimate of hypoperfusion. (3) The PWI/DWI mismatch with TTP >4 seconds did not reliably correspond to the penumbra as assessed by PET (oxygen extraction fraction >150%). Only 6 of 10 patients with a mismatch had areas of penumbra. In these cases, the penumbra volume was overestimated by MRI. DWI correlates with FMZ results and, with a few exceptions, yields a good estimate of acute tissue damage and final infarct volume. PWI measures seem to be less reliable; the TTP prolongation of >4 seconds assessed only 83% of the volume of hypoperfusion <20 mL/100 g per minute. The mismatch volume imprecisely depicts increased oxygen extraction fraction, and, despite its clinical role for selection of patients for eventual therapy, it does not to seem to be a reliable correlate of penumbra.