Chapter 12 examines the methodological foundations for conducting effective brain imaging research, positioning experimental design as the cornerstone of meaningful neuroscientific inquiry. It outlines a systematic approach to developing experiments, beginning with the essential groundwork of literature review and theoretical development before proceeding to stimulus creation and experimental implementation. The chapter emphasizes the critical balance between simplicity and complexity in design, advocating for well-controlled paradigms that isolate specific cognitive processes while acknowledging the brain’s inherent complexity. Particular attention is given to the technical considerations unique to different imaging modalities, addressing how fMRI’s hemodynamic response requires different design considerations than EEG’s direct measurement of neural activity. The chapter explores the philosophical challenges of constructing appropriate control conditions that effectively isolate the cognitive processes of interest, comparing cognitive subtraction approaches with factorial designs that reveal interaction effects. It emphasizes the importance of piloting experiments to identify potential confounds like expectancy bias and the role of jittered intertrial intervals in minimizing such effects. Throughout, the chapter underscores that experimental design in neuroimaging requires interdisciplinary expertise: understanding of brain anatomy and physiology, mastery of imaging technology, and sophisticated experimental psychology skills to translate abstract cognitive concepts into operationalizable experimental paradigms.