Funding multi-institution centers of research excellence (CREs) has become a common means of supporting collaborative partnerships to address specific research topics. However, there is little guidance for those planning or managing a multi-institution CRE, which faces specific challenges not faced by single-institution research centers. We conducted qualitative research to identify the challenges faced by an Australian program of multiinstitution CREs with a view to identifying lessons for the future. This paper describes two of the most significant challenges: administrative complexity and investigator engagement. Administrative tasks (e.g.: establishing partner contracts and recruitment) were significantly more complex and time-consuming in the multi-institution CREs than single-institution research centers. Investigator engagement was hampered by a range of factors, including differing expectations within the investigator team and between the team and the funding body in relation to investigator roles as well as investigator capacity. We conclude with a discussion of key strategies that cut across the challenges: 1) early planning, 2) communication and 3) management capacity.