This paper reflects on the potential of future-oriented analysis (FTA) to address major change and to support decision-makers and other stakeholders in anticipating and dealing with transformations. It does so by critically reflecting on the selected papers for this special issue as well as on the discussions that took place at the fourth Seville International Conference on Future-oriented Technology Analysis. Considering the potential roles of FTA in enabling a better understanding of complex situations and in defining effective policy responses leads to the understanding that appropriate FTA practices are needed to enable FTA to fulfil such roles. Dealing with disruptive changes - and grand challenges in particular -, therefore, raises several conceptual, methodological and operational issues. Two of them are general, while further two are specific to the so-called grand challenges: i) distinguish known unknowns, unknown knows and unknown unknowns, ii) combine quantitative and qualitative approaches in a relevant and feasible way, iii) understand the complex and systemic nature of grand challenges, and iv) orchestrate joint responses to grand challenges. After a brief explanation of these issues, the paper outlines the main ideas of the papers published in this special issue. These present various methodological aspects of FTA approaches as well as some advances needed in practice to assist FTA practitioners and stakeholders in comprehending transformations and in tackling the so-called grand challenges.