The human development paradigm like many other development policy domains, old and new, is being challenged by a fundamentally new context that has been described by many as a VUCA world meaning Volatile, Uncertain, Complex, and Ambiguous. These factors are of course not independent of each other, but interactive, thus making for a very difficult environment in which public policy must be made. The Human Development Report (HDR) made a wise and topical choice therefore in selecting uncertain unsettled lives as the theme for the 2021–2022 report. This paper first identifies some of the strengths of the current human development policy analysis but then proceeds to outline multiple concrete, though novel, ways of addressing the challenges of uncertain times and unsettled lives. These include the need for unpackaging the concept of uncertainty, highlighting both differences and linkages between risk and uncertainty, and further implications for policymaking. In addition, we discuss new and promising ways of thinking about uncertainty in policy issues around human development including complexity theory and complex adaptive systems thinking as well as quantum-like frameworks. Finally, we discuss applied spirituality which, in our opinion, can be of great value in engaging with unsettled lives. Ours is an attempt to call for a future paradigm in policy thinking, and social and human sciences as a whole