In this study, I aim to understand business responses to social-ecological grand challenges. Prior research has suggested that problem identification and attribution help to foster meaning and action on societal issues. In particular, framing theory has offered significant insight into individual actors' cognitive processes, their skillful articulation of socially resonant interpretive frames, and the role of particular actor categories and repertoires in framing success. At meso and macro levels, researchers have tended to focus on social movements and the outcomes of highly charged political contests between these groups and state actors. As such, we know far less about the co-creative mechanisms and contextual ‘raw materials' that underpin meaning making activities and interaction between groups, especially in instances where the focus is on firms and the significance being attached to ambiguous societal issues for which they are not directly responsible. A key outstanding question is therefore: how do firm-internal agents interpret, signify and mobilize organizational responses to grand challenges? In an effort to address these lacunae, this study explores the proactive efforts of three firms to interpret the complexity of social-ecological grand challenges that they share with the rest of society and to address these issues through meaningful and mitigating action. My inductively derived theoretical model of ‘interactional framing for issue advancement' shows how the active engagement of external influences by internal change or ‘signifying agents' facilitates action on grand challenges within and beyond the firm. While framing activities charge grand challenge issues with meaning and help to organize actors' understanding of, experience, and action around these issues, material affordances and interaction with external actors provide the enabling environment for resonant interpretations to take hold and to facilitate enactment. Grounded in my cases, the model also depicts the progressive sequencing of signifying agent efforts across three broad stages: Introduction and Disruption, Experimentation, and Enactment. My analysis contributes to the management literature by suggesting that the signification work of firm-internal agents is a process of mediation, shaped by the distinct and emergent character of grand challenges and the interplay of social and material mechanisms. Because such issues require a greater emphasis on problem-solving and novel sources of information, my account contrasts with conventional representations of meaning-making as a relatively straightforward line of action from individual logics ‘pulled down' from institutional systems and packaged attractively to appeal to ‘outsiders' less involved in the processes of signification. It also provides an alternative to the popular view of meaning construction as a ‘contest' or essentially dispute-oriented process. Instead, I argue that grand challenge issue advancement demands a more intricate, interactional and contextual process of meaning-making by interested actors and issue proponents internal and external to the firm. The model of signification work I offer in this study thus more fully captures the perspective that actors do not simply assess and attach importance to complex issues, but construct the very nature of the issue itself, and that this construction is a precursor to collaborative action on grand challenges.