This study identifies mutations in the *UBQLN2* gene as the cause of dominant X-linked juvenile and adult-onset amyotrophic lateral sclerosis (ALS) and ALS/dementia. The *UBQLN2* gene encodes ubiquilin2, a protein involved in protein degradation. The authors identified a five-generation family with ALS, including 19 affected individuals, where the disease was transmitted in a dominant fashion with reduced penetrance in females. Linkage analysis and sequencing identified a unique mutation, c.1490C>A (p.P497H), in *UBQLN2* in this family. This mutation was also found in four other unrelated families with ALS or ALS/dementia. Pathological analysis revealed ubiquilin2 pathology in the spinal cords of ALS cases and in the brains of ALS/dementia cases, both with or without *UBQLN2* mutations. Functional studies showed that the *UBQLN2* mutations impair ubiquitin-mediated proteasomal degradation. These findings suggest that abnormalities in ubiquilin2 may contribute to the pathogenesis of ALS and ALS/dementia by disrupting protein degradation and leading to neurodegeneration.This study identifies mutations in the *UBQLN2* gene as the cause of dominant X-linked juvenile and adult-onset amyotrophic lateral sclerosis (ALS) and ALS/dementia. The *UBQLN2* gene encodes ubiquilin2, a protein involved in protein degradation. The authors identified a five-generation family with ALS, including 19 affected individuals, where the disease was transmitted in a dominant fashion with reduced penetrance in females. Linkage analysis and sequencing identified a unique mutation, c.1490C>A (p.P497H), in *UBQLN2* in this family. This mutation was also found in four other unrelated families with ALS or ALS/dementia. Pathological analysis revealed ubiquilin2 pathology in the spinal cords of ALS cases and in the brains of ALS/dementia cases, both with or without *UBQLN2* mutations. Functional studies showed that the *UBQLN2* mutations impair ubiquitin-mediated proteasomal degradation. These findings suggest that abnormalities in ubiquilin2 may contribute to the pathogenesis of ALS and ALS/dementia by disrupting protein degradation and leading to neurodegeneration.