Adaptation is the pursuit of active, deliberate measures to enhance humankind’s capacity to manage water supply and attenuate demand in the face of climate uncertainty. This article contends that worsening constraints upon freshwater due to climate variability demand concerted, imaginative, science-based solutions. These solutions must join creative management to co-production of climate knowledge. Through a series of case studies, we analyze the need for adaptation approaches to prevail over climate variability, and the role of these factors to facilitate their implementation. We also examine how translation of climate knowledge is helping spur adaptation at various spatial levels. These experiences point to the challenges in adaptation, and the adversity various regions will be faced if we do not.