Neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) are characterized by chronic and progressive neuronal loss. Being able to detect and quantify neurodegeneration is the first step to identify mechanisms underlying neuronal cell death and to develop novel therapeutic strategies. In this chapter, we describe a practical method for detecting and quantifying neurodegeneration in adult and aging mouse brains based on protocols developed in our laboratory over the last decade. We include protocols on sample preparation, immunohistochemical analysis, and stereological methods for counting neurons using examples of AD and PD mouse models. We also describe how to use Fluoro-Jade staining and terminal deoxynucleotidyl transferase dUTP nick end labeling to detect degenerating neurons and apoptotic cells, respectively, and how to use specific proteins as early markers of neurodegeneration.