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Why do regional institutions emerge, what accounts for their variation in design, and what are their effects? Several conceptual and epistemological perspectives—neorealism, neoliberal-institutionalism, constructivism, and domestic politics—provide competing and complementary answers to these questions. I focus on regional organizations as productive arenas for developing contingent propositions on institutions more generally. The purpose is to advance cross-paradigmatic dialogue in two ways: through sensitivity to scope conditions and to institutional genesis, forms, and effects, in an effort to transcend axiomatic debates that often conflate different dependent variables. The empirical analysis includes the Association of Southeast Asian Nations (ASEAN), Asia-Pacific Economic Cooperation (APEC), ASEAN Regional Forum (ARF) and the Arab League. The main findings from these cases suggest that understanding the nature of dominant domestic coalitions is often crucial for explaining incentives to create, design, and fine-tune the effects of institutions. However, this is mainly the case when the consequences of creating or designing institutions for power distribution, transaction costs, and norms are negligible or hard to estimate. In many cases these consequences are sizeable, reducing the explanatory influence of domestic coalitions. The latter often provide no more than permissive conditions for the emergence, design, and effect of institutions. Their influence is most decisive in explaining institutional genesis but is often underdetermining in explaining their design.