In this paper, we illustrate the link between social network structures, dominant cognitive frames on network purpose and the innovative power of a network, through a mixed-method comparative analysis of two knowledge translation networks (KTNs) in the English National Health Service (NHS). Our findings illustrate several challenges for networked forms of organization linked to different manifestations of social networks (centralized/decentralized) and dominant cognitive frames (polarizing/loosely clustered). Our paper contributes a better understanding of how dominant frames on network purpose emerge alongside the development of network structure itself, and explores how this interplay between dominant frames and social networks impacts upon the collaborative work that supports the network’s innovative power.