This paper examines the evolving situation of mature manufacturing small and midsize enterprises (SMEs) in Japan and the United States and considers some of the key challenges they now face in an era of globalization and rapid technological change. The rationale and justification for policy intervention to support mature SMEs is considered. A review is offered of illustrative policy initiatives in three areas: framework policies, industrial services, and regional industrial cluster policies. The convergence of manufacturing and regional policies is noted. The relative strengths and weaknesses of Japanese and US strategies are assessed. The paper concludes with a comparison of Japanese and US approaches to retaining manufacturing SMEs, interpreted through the various and at times interactive ways through which each country’s innovation system develops and evolves technology and business support policies.