Functional magnetic resonance imaging (fMRI) maps the spatiotemporal distribution of neural activity in the brain under varying cognitive conditions. Since its inception in 1991, blood oxygen level-dependent (BOLD) fMRI has rapidly become a vital methodology in basic and applied neuroscience research. In the clinical realm, it has become an established tool for presurgical functional brain mapping. This chapter has three principal aims. First, we review key physiologic, biophysical, and methodologic principles that underlie BOLD fMRI, regardless of its particular area of application. These principles inform a nuanced interpretation of the BOLD fMRI signal, along with its neurophysiologic significance and pitfalls. Second, we illustrate the clinical application of task-based fMRI to presurgical motor, language, and memory mapping in patients with lesions near eloquent brain areas. Integration of BOLD fMRI and diffusion tensor white-matter tractography provides a road map for presurgical planning and intraoperative navigation that helps to maximize the extent of lesion resection while minimizing the risk of postoperative neurologic deficits. Finally, we highlight several basic principles of resting-state fMRI and its emerging translational clinical applications. Resting-state fMRI represents an important paradigm shift, focusing attention on functional connectivity within intrinsic cognitive networks.