In this study we explain the puzzle of insular domains: insular domains are niches where new innovation is built on the knowledge within the domain. Given the nature of knowledge needed for new innovation in an insular domain the puzzle is why do new firms enter these niches? In a longitudinal sample of 128 biotechnology start-ups founded from 1980 to 1999 we explain why start-ups enter insular domains and how the start-ups develop technology capabilities.