The term frontotemporal dementia (FTD) refers to a group of neurodegenerative disorders caused by impairment of neuronal networks centered in the frontal and temporal lobes. Imaging and pathology studies indicate an important role of the cortex in FTD. Each FTD syndrome is associated with degeneration of specific cortical regions. Neuronal loss and pathological inclusions are particularly prevalent in cortical layers 2 and 3 in many patients. Additionally, specialized populations of neurons located in the frontoinsular and anterior cingulate cortices are among the first neurons lost in the most common FTD clinical subtype. As much as 25% of FTD is dominantly inherited, and the genetic causes of these cases have been used to generate experimental models of FTD. In this chapter, we discuss the degeneration of neuronal networks in each FTD syndrome and how experimental models have provided insight into the molecular mechanisms underlying FTD, thus revealing potential therapeutic targets.