GGGGCC (G4C2) hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) has been identified as the most common genetic abnormality in both frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). To investigate the role of C9ORF72-related G4C2 repeat expansion in ALS and FTLD, several animal and cell culture models have been generated that reveal initial insights into the disease pathogenesis of C9 ALS/FTLD. These models include neurons differentiated from patient-derived pluripotent stem cells as well as genetically engineered cells and organisms that knock down C9ORF72 orthologues or express G4C2 repeats. Targeted reduction or knockdown of C9ORF72 homologues in zebrafish and mice so far produced conflicting results which neither rule out, nor confirm reduced expression of C9ORF72 as a pathogenic mechanism in C9 ALS/FTLD. In contrast, studies using patient-derived cells, as well as Drosophila and zebrafish models overexpressing disease-related hexanucleotide expansions, can cause repeat length-dependent formation of RNA foci, which directly and progressively correlate with cellular toxicity. RNA foci formation is accompanied by sequestration of specific RNA-binding proteins (RBPs), including Pur-alpha, hnRNPH and ADARB2, suggesting that G4C2-mediated sequestration and functional depletion of RBPs are cytotoxic and thus directly contribute to disease. Moreover, these studies provide experimental evidence that repeat-associated non-ATG translation of repeat-containing sense and antisense RNA leads to dipeptide-repeat proteins (DPRs) that can accumulate and aggregate, indicating that accumulation of DPRs may represent another pathogenic pathway underlying C9 ALS/FTLD. These studies in cell and animal models therefore identify RNA toxicity, RBP sequestration and accumulation of DPRs as emerging pathogenic pathways underlying C9 ALS/FTLD.