The International Institute for Applied Systems Analysis (IIASA) held its 40th Anniversary Conferencein October 2012. As a follow-up to the insightful presentations and discussions at the conference, it was decided to publish some of the research highlights as a special  issue in this journal. Building upon IIASA's scientific foundations and agenda, this special issue has two major themes: Dealing with uncertainty in integrated analyses of human-environment systems; Social, technical and institutional transformatons in response to  global sustainability challenges. Several papers illustrate methodological advances in dealing with uncertainties with practical applications related to major global and regional challenges such as food security, greenhouse gas emission reductions and moving towards  green economy. Other papers illustrate a range of advances regarding multiple transformations and their versatile interconnected impacts with practical applications related to major global challenges such as growing population, geenhouse gas emission  reductions and involving stakeholders in policy-making.