Spinocerebellar ataxia type 1 (SCA1) is a late onset neurodegenerative disease characterized by cerebellar ataxia with variable degrees of ophthalmoplegia, pyramidal and extrapyramidal signs, and peripheral neuropathy. SCA1 is caused by the toxic effects triggered by an expanded polyglutamine (polyQ) within the protein ataxin 1 (Atxn1) resulting in variable degrees of neurodegeneration in the cerebellum, brainstem, and spinocerebellar tracts. The toxic gain-of-function mechanisms by which the polyQ expansion induces neuronal cell death are not fully understood and no effective therapies are yet available. Alterations in transcriptional regulation, calcium homeostasis, glutamate signaling/excitotoxicity, and impaired protein degradation are few recurrent events in the pathogenesis in SCA1. However, elucidating the molecular routes regulated by ataxin 1 is leading to the discovery of new pathways that are implicated in SCA1. This suggests that dominant-negative effects exerted by the mutant protein, rather than just gain-of-function mechanisms, might be also implicated in SCA1 pathogenesis. The challenge now is to determine how these responses account for the clinical manifestation of the disease symptoms and, ultimately, how this knowledge can be translated into the development of therapeutic strategies. Herein, we review the phenotype and most recent advances in our understanding of the physiopathological mechanisms of neurodegeneration in SCA1.