Nearly two decades have passed since the Triple Helix (TH) framework was introduced as an important mechanism of industrial and regional development. Originating in the "New Production of Knowledge" discourse (Gibbons, 1994) but developed by Leydesdorff and Etzkowiz (1998), the underlying theme of the TH framework is that knowledge and innovation are best generated, sustained and disseminated through the interactions of industry, academia and public institutions. In terms of industrial and regional policies, the TH approach largely focuses on local/regional/national interactions with the goal of knowledge building and dissemination to counterbalance global challenges (see, e.g. Leydesdorff. & Etzkowitz, 1996; Leydesdorff, & Etzkowitz, 1998; Nuur et al, 2013). The TH framework allocates Institutions of Higher Education a primary role (Etzkowitz & Klofsten, 2005; Assbring and Nuur, 2017). From a regional development perspective, the TH framework maybe viewed as contributing to a synthesis of how innovations are generated and disseminated. It is a more prescriptive to adopt and use as a platform for channeling resources (Smith & Bagchi, 2010, Gustavsson et al, 2016) involving local industries and regional universities. Given that the dynamics can be found in the interaction between the three main actors (or families of the key players) the TH visions that the three players jointly add to innovation system (Etzkowitz, 2003). This paper focuses on the role of institutions of higher education when put in the context of regional universities. It identifies some of the challenges that regional universities face in embracing the TH framework in their strategies. Based on four case studies of regional universities in Sweden, the paper argues that the implementation of TH framework is not about a one-size fit all. Instead, it is vital that the TH approach should be framed in different ways depending on the regional context.