This chapter discusses some important methodological considerations underlying resting‐state functional MRI (rsfMRI) along with various analytical strategies, including both standard and more novel approaches. The discussion is then followed by a heuristic framework describing the emergence of a large‐scale network approach to understanding addiction neurobiology. The chapter highlights additional challenges and future directions required for rsfMRI to provide a valuable system‐level biomarker of disease severity, treatment matching, and outcome prediction. Blood oxygenation level‐dependent (BOLD) imaging has been widely used in rsfMRI studies, likely due to its high sensitivity and ease of implementation. Neuronal activity is accompanied by corresponding changes in glucose and oxygen consumption, which are supported by blood circulation. Gradient‐echo planar imaging (EPI), the most commonly used imaging sequence in BOLD‐based fMRI, is sensitive to artifacts at the interfaces of brain tissue and air or bone due to inhomogeneous magnetic fields generated by susceptibility differences of two adjacent materials.