Abstract: Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative diseases that belong to the same disease spectrum, with overlapping of genetic and pathological features. Genetic mutations in TARDBP, C9ORF72, MAPT, and GRN have been identified in these diseases. The TARDBP gene encodes transactive response DNA binding protein 43 kDa (TDP-43), and abnormal deposition of TDP-43 is present in approximately 50% of FTD and 95% of ALS (Neumann et al., 2006). It is present as native TDP-43, phosphorylated TDP-43 (pTDP-43), and other truncated forms. C9ORF72 is the most common genetic abnormality implicated in behavioral-variant FTD (bvFTD), and in approximately 40% of familial ALS. The number of C9ORF72 G4C2 hexanucleotide repeats in healthy individuals is approximately 2–20, whereas in bvFTD and ALS hundreds or thousands. The second most common pathological protein aggregation in FTD is the MAPT gene product tau. Over 50 MAPT mutations have been identified in FTD. Abnormal accumulation of SOD1 is the second most common pathology in ALS, and a number of SOD1 mutations have been identified in ALS. Heterozygous mutations in GRN lead to autosomal-dominant FTD, which is associated with TDP-43 deposits, as well as other pathologies. Similar pathologies resulting from these mutations, as well as similar or overlapping clinical features between the two diseases and their subtypes, underscore the importance of developing biomarkers for FTD and ALS. Peripheral biomarkers would flag cases at the pre-symptomatic stage, facilitate more accurate diagnosis and differential diagnosis of diseases or disease subtypes, predict the progression and prognosis of diseases, and monitor the effects of therapeutic interventions (Figure 1). At present, there are no definitive biomarkers that serve these purposes in FTD and ALS. However, recent progress in biomarker development has identified candidates with improved biomarker potential.