One of the goals of human functional imaging studies is to interpret brain activation in the context of an individual's subjective experience. However, functional magnetic resonance imaging (fMRI) studies usually employ a block design that consists of multiple epochs of stimulation; this strategy does not readily allow subjective responses to be assessed on a stimulus-by-stimulus basis. To address this issue, we developed a "single-epoch" design, consisting of a single stimulation period presented between two baseline periods. This allows subjective ratings to be acquired after each stimulus, while minimizing rating-induced confounds. To evaluate its sensitivity and utility, we obtained fMRI data using single-epoch and block designs (five stimuli between six baselines) and assessed regional brain activations evoked by both visual (a checkerboard pattern) and painful (noxious heat to right calf) stimuli. For both types of stimulation, data collected using the single-epoch design displayed activation patterns that were generally similar to those detected with the block design. Furthermore, only one single-epoch acquisition series was sufficient to detect bilateral activation in the visual cortex during visual stimulation and activation in the primary somatosensory cortex, the anterior cingulate cortex, and other regions during painful stimulation. In addition, analyses of a series of single-epoch data from a single individual revealed a stimulus-by-stimulus decrease in the activation in the anterior cingulate cortex that paralleled the decrease in the subject's psychophysical responses. These findings confirm that the single-epoch design is sensitive to regional signal changes and serves as a viable alternative to the block design when the collection of subjective responses is of critical importance.