Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders that share clinical, pathological, and genetic overlap, most notably through mutations in the C9orf72 gene. Since its discovery in 2011, this mutation has emerged as a key driver of neurodegeneration through a complex interplay of toxic gain-of-function and loss-of-function mechanisms. The repeat expansion disrupts RNA metabolism, proteostasis, and nucleocytoplasmic transport, while impairing autophagy and endolysosomal trafficking due to reduced C9orf72 protein expression. Concurrently, bidirectional transcription of repeat-containing RNA generates RNA foci and dipeptide repeat proteins via repeat-associated non-AUG translation, sequestering RNA-binding proteins and inducing cellular stress. These processes converge on neuroinflammation, mitochondrial dysfunction, and TDP-43 proteinopathy—culminating in a rapidly progressive clinical phenotype with frequent cognitive involvement. This review synthesizes recent mechanistic, clinical, and therapeutic advances in C9orf72-associated ALS/FTD. It highlights the growing relevance of biomarkers such as neurofilament light chain and poly-GP, the failure of antisense oligonucleotide therapy (BIIB078) to modify TDP-43 pathology despite adequate CNS penetration, and the promise of emerging approaches, including allele-specific CRISPR-Cas9 editing, autophagy modulation, and inflammasome inhibition. Future research must integrate multi-omics datasets, patient-derived organoids, and advanced preclinical models to clarify the relative contributions of gain- and loss-of-function mechanisms. Bridging these insights with precision medicine frameworks offers the most compelling path toward mechanism-driven interventions capable of altering the natural course of C9orf72-related neurodegeneration.