Recent works have demonstrated an expansion of the GGGGCC hexanucleotide repeat in the first intron of chromosome 9 open reading frame 72 (C9ORF72), encoding an unknown C9ORF72 protein, which was responsible for an unprecedented large proportion of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) cases of European ancestry. C9ORF72 is expressed in most tissues including the brain. Emerging evidence has demonstrated that C9ORF72 mutations could reduce the level of C9ORF72 variant 1, which may influence protein expression and the formation of nuclear RNA foci. The spectrum of mutations is broad and provides new insight into neurological diseases. Clinical manifestations of diseases related with C9ORF72 mutations can vary from FTD, ALS, primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), Huntington disease-like syndrome (HDL syndrome), to Alzheimer's disease. In this article, we will review the brief characterizations of the C9ORF72 gene, the expansion mutations, the related disorders, and their features, followed by a discussion of the deficiency knowledge of C9ORF72 mutations. Based on the possible pathological mechanisms of C9ORF72 mutations in ALS and FTD, we can find new targets for the treatment of C9ORF72 mutation-related diseases. Future studies into the mechanisms, taking into consideration the discovery of those disorders, will significantly accelerate new discoveries in this field, including targeting identification of new therapy.