Uncertainty derives from the intertwining of ontological and epistemic conditions. The relationship between those two sets of conditions emerges as a unifying theme of this volume. Taken in their unity, the different contributions acknowledge that the configuration of any given situation (state of the world) determines whether or not the corresponding epistemic grasp is grounded; they also recognize that the epistemic context may be central in determining whether or not a grounded understanding of that situation is feasible. This point of view is common to the different contributions in the volume and suggests a pragmatic attitude towards uncertain real-world situations and epistemic contexts. This means that the handling of uncertainty cannot be left to a single standard criterion for the description (circumscription) of situations, nor can it be achieved by a uniform rule for the revision of inductive knowledge. Rather, uncertainty calls for agents capable of producing both situation-adequate descriptions and sophisticated inferences. This volume emphasizes that such a need becomes greater as we move towards fundamental uncertainty. It is important to emphasize that the above requirement does not make for arbitrariness in the handling of uncertainty. On the contrary, it would be necessary, in each case, to identify a suitable intersection of ontological and epistemic conditions, and this intersection would normally narrow down the number of relevant ontological and epistemic states. In short, constraints on plausible judgement are increasingly binding as uncertainty increases either for ontological or epistemic reasons (or for both). At the same time, the need to meet multiple relevance conditions (both on the ontological and the epistemic side) discloses the manifold opportunities associated with negative heuristics, that is, with a discovery and choice strategy in which descriptions and/or arguments are gradually discarded as one moves from one reasoning step to another. To conclude, fundamental uncertainty points to a requirement of extended rationality and highlights that prudence may be essential in the application of it.