Frontotemporal lobar degeneration (FTLD) comprises two main classes of neurodegenerative diseases characterized by neuronal/glial proteinaceous inclusions (i.e., proteinopathies) including tauopathies (i.e., FTLD-Tau) and TDP-43 proteinopathies (i.e., FTLD-TDP) while other very rare forms of FTLD are known such as FTLD with FUS pathology (FTLD-FUS). This review focuses mainly on FTLD-Tau and FLTD-TDP, which may present as several clinical syndromes: a behavioral/dysexecutive syndrome (behavioral variant frontotemporal dementia); language disorders (primary progressive aphasia variants); and motor disorders (amyotrophic lateral sclerosis, cortico-basal syndrome, progressive supranuclear palsy syndrome). There is considerable heterogeneity in clinical presenta-tions of underlying neuropathology and current clinical criteria do not reliably predict underlying proteinopathies ante-mortem. In contrast, molecular etiologies of hereditary FTLD are consistently associated with speciﬁc proteinopa-thies. These include MAPT mutations with FTLD-Tau and GRN, C9orf72, VCP and TARDBP with FTLD-TDP. The last decade has seen a rapid expansion in our knowledge of the molecular pathologies associated with this clinically and neuropathologically heterogeneous group of FTLD dis-eases. Moreover, in view of current limitations to reliably diagnose speciﬁc FTLD neuropathologies prior to autopsy, we summarize the current state of the science in FTLD biomarker research including neuroimaging, bioﬂuid and genetic analyses. We propose that combining several of these biomarker modalities will improve diagnostic speci-ﬁcity in FTLD through a personalized medicine approach. The goals of these efforts are to enhance power for clini-cal trials focused on slowing or preventing progression of spread of tau, TDP-43 and other FTLD-associated patholo-gies and work toward the goal of deﬁning clinical endophe-notypes of FTD.