- MSME development has emerged at the forefront of economic policy, with the majority of policy mechanisms aimed at creating the regulatory and institutional environments, which have historically proven to augment entrepreneurial activity. In the case of Europe a large portion of entrepreneurial policy resides within the European Community framework, however the effectiveness of such centralized structuring remains in question, particularly in regard to inspiring European Union (EU) economies of South Eastern Europe (SEE), which have differing economic and cultural foundations. This study aims to identify the regional role of economics, regulation and culture in motivating entrepreneurship in an effort to better guide economic policy decisions. Using SEE as a regional case study against the backdrop of the larger EU population and policy framework, the analysis concentrates on cultural indicators of corruption, perceived ‘needs’, collectivist mindset, risk adverseness, and institutional weariness influences on entrepreneurialism. Through the analysis regional variance among entrepreneurial drivers was discovered, however direct influences, with consideration for all factors of regulation, economics and culture, remained inconclusive. In response to such results, the study paid particular attention to the change in cultural influence with the inclusion of specific economic and regulatory variables, finding that such inclusion reduces the importance of culture on entrepreneurship, thus lending to a conclusion that identifies regulation and economic variables as direct influences to entrepreneurship, with culture as a potential indirect factor that is both affected by other independent variables and indirectly affects entrepreneurship. The conclusions of the study do not dismiss the relevance of regulatory and institutional directed policy, but rather reconfirm the ongoing need to integrate regional factors related to culture into centralized entrepreneurial policy in order to ensure that a robust policy model is examined and effectively deployed within SEE.