Brain function has traditionally been studied in terms of physiological responses to environmental demands. This approach, however, ignores the fact that much of the brain's energy is devoted to intrinsic neuronal signaling. Recent studies indicate that intrinsic neuronal activity manifests as spontaneous fluctuations in the blood oxygen level-dependent (BOLD) functional MRI (fMRI) signal. The study of such fluctuations could potentially provide insight into the brain's functional organization. In this article, we begin by presenting an overview of the strategies used to explore intrinsic neuronal activity. Considering the possibility that intrinsic signaling accounts for a large proportion of brain activity, we then examine whether the functional architecture of intrinsic activity is altered in neurological and psychiatric diseases. We also review a clinical application of brain mapping, in which intrinsic activity is employed for the preoperative localization of functional brain networks in patients undergoing neurosurgery. To end the article, we explore some of the basic science pursuits that have been undertaken to further understand the physiology behind intrinsic activity as imaged with BOLD fMRI.