How can social science and historical approaches combine in order to enrich the regional studies theme? This chapter focuses on designs for small-N comparative research, specifically the problem of how to apply systematically structured synchronic and diachronic comparisons as a means to analyze interdependence. We hold that comparative sequence design (CSD) poses an important methodological option in that perspective. In contrast to standard research designs, such as cross-sectional design and development design (“historical case studies”), CSD allows for both systematic (i) cross-unit and cross-case comparisons as well as (ii) within-unit analyses. It (iii) opens up for the use of process-oriented models with a focus on explaining developmental outcomes among sub-national level units, and thereby (iv) facilitates analysis of both spatial, temporal and temporal-spatial interdependence among sub-national level units (regions). CSD provides a tool for examining e.g. policy-making and policy diffusion as dynamic, historically contingent processes; and, from the perspective of the historical disciplines, allows analysts to move beyond the limits of traditional case studies of regions and localities.