Many studies have focused on retrospectively identifying critical success factors (CSFs) for healthcare information system (HIS) development projects. In this paper the central question is how in advance selected CSFs can be applied in the best way. An action research study has been carried out in a large Swedish healthcare organization during 2010 and 2011 where the application of four CSFs has been planned, documented and reflected upon. Challenges are identified that may arise when tailoring general CSFs to situational circumstances. For example, the self-evident CSF of ?having a clear and accepted objective? becomes tricky and complex in practice when facing 15 autonomous boards that all need to support the project. Similar insights are gained for other CSFs. More research is needed to illuminate the complexities of how to apply CSFs. Another important observation is that different CSFs strengthen one another, which implies that they should be applied and analysed in concert rather than isolated. Finally, healthcare practitioners need to be aware that CSFs are very helpful, but that tailoring general CSFs to the unique situation of the HIS development project requires much effort and continuous reflection from a holistic perspective embedded in systems thinking.