Together with founders and representatives of long-term global twin-family registers, we sought to uncover the keys to establishing, operating, sustaining, and expanding twin registers. Through a series of targeted questions posed to register leaders, we aimed to distill their collective wisdom, providing valuable guidance for researchers embarking on similar endeavors. Twin registers serve as invaluable resources in multiple domains of human research. Over time, their longitudinal data collections have evolved into extensive repositories, spanning decades of data collection and encompassing diverse aspects of human health and behavior. By synthesizing the shared experiences and strategies of twin register pioneers, this chapter offers an overview of best practices and challenges encountered in the establishment and maintenance of twin registers. It underscores the pivotal role of longitudinal studies within these registers, highlighting the inclusion of not only twins but also their extended family members. We hope this chapter serves as a resource for researchers seeking to harness the full potential of twin registers in advancing scientific inquiry and understanding the complexities of human health and behavior.