Most cases of frontotemporal lobar degeneration (FTLD) are characterized by the abnormal accumulation of either the microtubule-associated protein tau or the transactive response DNA-binding protein with M(r) 43 kDa, TDP-43 (FTLD-tau and FTLD-TDP, respectively). However, there remain ∼10% of cases, composed of a heterogenous collection of uncommon disorders, for which the molecular basis remains uncertain. In this review, we describe the characteristic genetic, clinical, and pathological features of the major tau/TDP-negative FTLD subtypes, with focus on recent advances in our understanding of their molecular basis. This includes the discovery that the pathological changes in atypical FTLD with ubiquitinated inclusions, neuronal intermediate filament inclusion disease, and basophilic inclusion body disease are immunoreactive for the fused in sarcoma (FUS) protein, resulting in the creation of a new molecular subgroup (FTLD-FUS), and studies clarifying the functional consequences of pathogenic CHMP2B mutations.