Huntington's disease (HD) is an inherited disorder characterized by neuronal dysfunction and degeneration in striatum and cerebral cortex. Although the signaling pathways involved in HD are not yet clearly elucidated, mutant huntingtin protein is a key factor in the induction of neurodegeneration. The mutant huntingtin protein alters intracellular Ca(2+) homeostasis, disrupts intracellular trafficking and impairs gene transcription. In this review, I emphasize the effects of mutant huntingtin protein in Ca(2+) handling and transcriptional factors. Transcriptional alterations are key factors in the deficits of several proteins involved in the cellular machinery. These proteins include neurotrophic factors such as brain-derived neurotrophic factor, fibroblast growth factor, glial-cell-line-derived neurotrophic factor, ciliary neurotrophic factor and neurturin that have been suggested to restore neuronal dysfunction, improve behavioral deficits and prolong the survival in animal models of HD. An understanding of the molecular pathways involved in neurodegeneration will shed light on the choice of neurotrophic factors targeting a specific neuronal population in HD and will consequently overcome behavioral deficits.