This chapter defines the main experimental designs possible with lesion methods and discusses both the strengths and weaknesses of these techniques. Lesion studies remain a crucial part of the experimental toolbox in this field because of the nature of evidence that can be obtained with this method. These studies offer particular inferential strengths, complementing other approaches. Human lesion studies are at best quasiexperimental. Most studies in affective neuroscience make use of novel behavioral measures and so usually require a reference group made up of healthy subjects demographically similar to the target patient population to help interpret the performance of the patient group. Region-of-interest (ROI) studies often involve both a healthy reference group and a brain-damaged control group. Lesion studies have made many interesting contributions to affective neuroscience and are especially important in building a converging evidence base for the brain basis of complex processes.