We have recently undertaken a five year international comparative study of Inter-organizational Information Systems (IOIS) in the pharmaceutical supply chain in four countries, with the initial aim of investigating the relationship between differences at the industry and national level and the structure of the IOIS in these countries. We found because of the large timescale (beyond individual projects) and the large scope of analysis (including firm, industry and national factors) that a new phenomenon of IOIS evolution came into our view. This paper presents the journey we have taken in re-evaluating appropriate theoretical underpinnings for studying and explaining IOIS phenomena at this large scale. We present our insights by relating the series of revisions we were forced by the phenomena to make to our research model, illustrated with two case vignettes.