Indigenous tribes of the interior Columbia River have developed a mutual relationship with native fishes since time immemorial. However, extensive disruption to the natural ecosystem has occurred as European settlement of North America extended westward to utilize abundant natural resources in ways that conflicted with millennia of indigenous protection. This anthropogenic disturbance has led to dramatic declines in native fish species that are central to tribal cultures, but efforts are underway to enable these fishes and the people that rely upon them to persist for future generations. Here, we describe how pairing indigenous knowledge and western science have been applied to assist with fisheries recovery in the Columbia River. Parallel understanding of information passed across generations is central to this effort, from tribal elders with their historical grasp of the natural ecosystem and fisheries, to molecular genetic approaches that track DNA that is passed from parents to offspring and subsequent generations. Examples are provided that illustrate how both indigenous knowledge and genetic tools have been applied to support fisheries recovery in the Columbia River Basin.