Craniofacial malformations affecting head and face can result in severe functional, esthetical, and social consequences for affected individuals. During the first funding period, CRANIRARE ascertained and clinically characterized a substantial number of patients with various craniofacial malformations, which enabled us to standardize clinical classifications, molecular diagnosis, and genetic counselling for these disorders. We successfully identified 18 novel causative genes for 13 different craniofacial disorders and elucidated new conserved molecular pathways important for biological processes of craniofacial development. Moreover, we developed novel technologies for local delivery of bioactive agents to induce bone tissue regeneration. CRANIRARE has received wide recognition on international level and we established a collaboration with the NIH-funded FACEBASE network for common activities und support. Relying on the established CRANIRARE infrastructure, we now aim to extend our work and include 15 additional craniofacial phenotypes (total of 19 phenotypes), to identify the causative genes, and to investigate conserved molecular pathways of identified proteins in cellular systems and zebrafish model. An innovative “next generation sequencing (NGS) education platform” will be established by all partners, aiming to improve transfer of knowledge and education on this high-end technology. We will translate our molecular findings into the establishment of new molecular diagnostic tests by the use of e.g. next generation sequencing and design new therapeutic options based on our novel insights into altered molecular pathways involved in craniofacial malformations. Different innovative dissemination activities are planned and the partners will educate young scientists and medical doctors during our CRANIRARE Summer School, which will further increase the sustained yield of the proposed CRANIRARE project. Continuation of our transnational collaborative work will greatly help to improve patient care of affected individuals by these rare diseases.