Why is it that Kyoto, ancient cultural capital of Japan, a conservative and traditional place in many ways, manages to produce Japan's most innovative (and profitable) high technology entrepreneurial firms? Further, what causes regions such as Kyoto to create a self-sustaining critical mass, or cluster, of new venture start-ups in emerging sectors? Can this success in 'clustering' entrepreneurial businesses be replicated elsewhere? For example, what are the most effective ways to encourage new start-ups and connect fledgling firms to critical resources? The findings herein are based primarily on original case study survey and interview data from 29 life science start-ups and the entrepreneurs at their helms, representing more than half of all life science start-ups in Kyoto. I identify best practices in firm-level strategy and entrepreneurship policy in what I call the Kyoto Model of Entrepreneurship and Innovation, highlighting entrepreneurial case studies of successful start-ups. I also analyze factors leading to successful new business clusterization through analysis of entrepreneurial social networks and resource environments. Situating the findings within national innovation and entrepreneurship policies in Japan, I present a new model for regional innovation systems (RIS) and cluster emergence. I also include brief comparisons to life science clusters (and want-to-be clusters) in Japan and the United States, based on additional original survey and interview research in other regional clusters in each country.