Implementing an Integrated Status and Trends Monitoring program (ISTM) for the mainstem Columbia River will help identify trends in important natural resources and help us understand the long-term collective effects of management actions. In this report, we present progress towards the completion of a stepwise process that will facilitate the development of an ISTM for the mainstem Columbia River. We discuss planning and regulatory documents that can be used to identify monitoring goals and objectives and present existing monitoring and research activities that should be considered as the development of a Columbia River ISTM proceeds. We also report progress towards the development of sample frames for the Columbia and Snake Rivers and their floodplains. The sample frames were formulated using Digital Elevation Models (DEM’s) of the river channel and upland areas and a Generalized Random-Tessellation Stratified (GRTS) algorithm for an area based resource to generate “master sample(s).” Working with the Pacific Northwest Aquatic Monitoring Partnership (PNAMP) we facilitated the transfer of the sample frames to the PNAMP “Monitoring Sample Designer” tool. We then discuss aspects of response and survey designs as they pertain to the formulation of a mainstem Columbia River ISTM. As efforts to formulate an ISTM for the mainstem Columbia River proceed, practitioners should utilize the extensive literature describing the planning and implementation of fish and wildlife mitigation and recovery efforts in the Columbia River Basin. While we make progress towards establishing an ISTM framework, considerable work needs to be done to formulate an ISTM program for the mainstem Columbia River. Long-term monitoring programs have been established for other large rivers systems; scientists that have experience planning, implementing, and maintaining large river monitoring efforts such as those in the Colorado, Illinois, and Mississippi Rivers should be consulted and involved as efforts proceed.