Over the past two decades, neuroimaging studies have defined a set of distributed brain systems that contribute to cognition, emotion, mood and other mental processes. Perturbations in these circuits have been identified in different ways across psychiatric and neurological disorders when comparing groups of patients to healthy individuals. Despite these advances, neuroimaging remains a correlative tool, largely incapable of determining the causal relationship between different task conditions (or groups of participants) and different brain activity states, correlational patterns or structural integrity. Hence, the challenge ahead of us is how to use these insights to: 1) establish the causal mechanisms regulating circuit function in health and illness, 2) elucidate the nature of neural circuit deficits in individual patients and their relevance for treatment, and 3) develop non-invasive circuit-based therapeutics. In this talk, I will introduce one method for accomplishing these goals in humans, namely the combination of non-invasive transcranial magnetic stimulation (TMS) with neuroimaging. Specifically, I will discuss simultaneous TMS and functional magnetic resonance imaging (TMS/fMRI) and electroencephalography (TMS/EEG). Both of these techniques, while technically challenging, offer an opportunity to causally probe and perturb focal brain function while simultaneously observing the consequence. I will review the basics of each method, important methodological characterizations and advances in data analytic approaches relevant for maximizing the utility of each method in both basic discovery as well as clinical application. I will close with illustrations of the novel insights possible by combining TMS with neuroimaging that would not be possible with each method alone. Based on these findings, I will argue that through these types of causal circuit mapping and manipulation methods we can now enter a new phase in human neuroscience whereby cause and effect can be more precisely determined, links to neurostimulation research in experimental animals can be more readily translated, and circuit-modifying interventions can be more rationally developed and tested.