The importance of characterizing, quantifying, and monitoring land cover, land use, and their changes has been widely recognized by global and environmental change studies. Since the early 1990s, three U.S. National Land Cover Database (NLCD) products (circa 1992, 2001, and 2006) have been released as free downloads for users. The NLCD 2006 also provides land cover change products between 2001 and 2006. To continue providing updated national land cover and change datasets, a new initiative in developing NLCD 2011 is currently underway. We present a new Comprehensive Change Detection Method (CCDM) designed as a key component for the development of NLCD 2011 and the research results from two exemplar studies. The CCDM integrates spectral-based change detection algorithms including a Multi-Index Integrated Change Analysis (MIICA) model and a novel change model called Zone, which extracts change information from two Landsat image pairs. The MIICA model is the core module of the change detection strategy and uses four spectral indices (CV, RCVMAX, dNBR, and dNDVI) to obtain the changes that occurred between two image dates. The CCDM also includes a knowledge-based system, which uses critical information on historical and current land cover conditions and trends and the likelihood of land cover change, to combine the changes from MIICA and Zone. For NLCD 2011, the improved and enhanced change products obtained from the CCDM provide critical information on location, magnitude, and direction of potential change areas and serve as a basis for further characterizing land cover changes for the nation. An accuracy assessment from the two study areas show 100% agreement between CCDM mapped no-change class with reference dataset, and 18% and 82% disagreement for the change class for WRS path/row p22r39 and p33r33, respectively. The strength of the CCDM is that the method is simple, easy to operate, widely applicable, and capable of capturing a variety of natural and anthropogenic disturbances potentially associated with land cover changes on different landscapes.