Background: For many questions asked by policymakers a substantial body of evidence exists. However, this evidence is often scattered and not available in a form that they can easily access. Systematic reviews (SRs) of health policy and systems research (HPSR) have the potential to contribute in summarising what is known about those questions. Although over the last two decades a reasonable consensus regarding ‘best practice’ for SRs informing clinical decision-making has been established, the research synthesis work in HPSR has been less developed. Objectives: To identify the methodological challenges in the conduct of SRs of HPSR in low and middle income countries (LMICs). Methods: A qualitative exploratory study using a convenience sample from the Alliance for HPSR sponsored project ‘Centres for Systematic Reviews of HPSR in LMICs’. The data were collected through a focus group with the Methodology Centre’s staff and semi-structured, in-depth telephone interviews with staff from the other Centres and the Alliance. The data were analyzed thematically, drawing on the Framework Approach. Results: There was not a clear distinction between methodological and practical/logistics challenges. Most of the challenges identified seem to be practical (low speed of internet connection, access to databases) while the methodological ones were not explicit or were solved with the support from other stakeholders. However, some areas where methodological development is needed were mentioned: scoping of the review questions, the use of ‘minor’ databases in HPSR, methods for the synthesis of different types of evidence. Conclusions: There is an urgent need to organize the relevant methodological challenges to advance in the field. An initial step should be the identification of other actors working on methodological issues related with HPSR and to collect and appraise the resources that they have developed. The identification of methodological gaps could allow the orientation of a future research agenda in the field.