Seen both as a resource and an obstacle to clarity, uncertainty is a concept that permeates many areas of design. As the concept gains prominence in Human-Computer Interaction (HCI), this special issue specifically explores the interplay between uncertainty and prototyping in Research through Design (RtD). We first outline three histories of uncertainty in design, in relation to its philosophical significance, its role in statistical and algorithmic processes, and its importance in prototyping. The convergence of these aspects is crucial as design evolves toward more agentive and entangled systems, introducing challenges such as Design as a Probabilistic Outcome. We then investigate the design spaces for engaging with “being uncertain” that emerge from the papers: from nuancing the relationship between designers and quantitative data to blurring the line between humans, fungi, and algorithms. Finally, we illuminate some preliminary threads for how RtD can navigate and engage with these shifting technological and design landscapes thoughtfully.