The clinical and pathological overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) suggests these diseases share common underlying mechanisms, a suggestion underscored by the discovery that TDP-43 inclusions are a key pathologic feature in both ALS and FTLD. This finding, combined with the identification of TDP-43 mutations in ALS, directly implicates this DNA/RNA binding protein in disease pathogenesis in ALS and FTLD. However, many key questions remain, including what is the normal function of TDP-43, and whether disease-associated mutations produce toxicity in the nucleus, cytoplasm or both. Furthermore, although pathologic TDP-43 inclusions are clearly associated with many forms of neurodegeneration, whether TDP-43 aggregation is a key step in the pathogenesis in ALS, FTLD and other disorders remains to be proven. This review will compare the features of numerous recently developed animal models of TDP-43-related neurodegeneration, and discuss how they contribute to our understanding of the pathogenesis of human ALS and FTLD.