Thermokarst lakes are abundant and highly dynamic landscape features of permafrost lowland regions in western Alaska and provide important ecosystem services as habitats, hydrological feature, biogeochemical hotspots, and for surface energy budgets. Permafrost in this ca. 300,000 km2 region follows approximately a North to South gradient of spatial continuity from continuous to sporadic permafrost zones, which also affects lakes and their dynamics on various temporal and spatial scales. Climate change in western Alaska has resulted in a significant warming of air and ground temperatures over the last decades and is projected to continue on that trajectory. To characterize the vulnerability of lakes as well as permafrost to climate change in this region, we assessed historic lake changes in major lake districts of western Alaska for the period ca. 1950 to ca. 2015 using various remote sensing approaches within a set of several independently funded studies. In particular, we were interested in the dynamics of lake growth and drainage in relation to permafrost degradation. Our method focused on the analysis of image time series built from the 30-60m resolution Landsat record for the 1970-2015 period. The observation period was further extended by unaltered historic USGS topographic maps that contain hydrology features and are based on aerial photography from ca. 1950. Our remote sensing studies were complemented by permafrost and lake hydrology field studies as well as aerial flights to validate remotely sensed lake drainage events. Additional validation of lake change was conducted locally with high resolution imagery from Spot-5, aerial photographs, and the DigitalGlobe constellation of satellites. Here, we synthesize the core results from these studies. The data was processed in three main categories. First we extracted water bodies from recent (2013-2015) Landsat-8 Observing Land Imager (OLI) images of the entire region using simple pixel threshold methods in ENVITM and compared these with waterbodies digitally extracted with ArcGISTM tools from unaltered historic (ca. 1950) USGS topographic map data to identify hotspots of lake change for the entire 65 year period. Second, we processed Landsat data covering major lake districts in the region from three time periods using an object-based segmentation and classification method specifically designed for lake extraction in eCognitionTM. Third, we applied a robust trend analysis developed with open source software and established image pre-processing algorithms to the entire Landsat-record for several large subregions to derive Tasseled Cap, NDVI, and NDWI land cover indices which are useful for studying annual trends in lake changes. Our findings suggest that a significant portion of lakes in this region has drained over the last decades and that in particular large lakes are vulnerable to disappearance. Initial analyses of relationships of lake drainages with permafrost distribution in the region suggest positive correlations between lake loss and permafrost degradation in much of the region. Our findings highlight that permafrost and lake-rich landscapes in Alaska are already changing rapidly and permanently in a warming world. This set of studies was supported by funding from NASA Carbon Cycle Sciences, NSF Arctic System Sciences, an European Research Council Starting Grant, and the Western Alaska Landscape Conservation Cooperative. Our study of lake dynamics in a thaw vulnerable permafrost landscape affected by climate change highlights the need for continuation of the Landsat mission as well as the increase of observation density with the new ESA Sentinel-2 mission.