Huntington's disease is a fatal neurodegenerative disorder caused by a mutation of the huntingtin gene and involves progressive motor abnormalities (including chorea), cognitive deficits (dementia) as well as psychiatric symptoms. We have previously demonstrated that environmental enrichment slows the onset and progression of Huntington's disease in transgenic mice. Here, we investigated the effects of enhanced physical exercise on disease progression and brain-derived neurotrophic factor expression. Standard-housed Huntington's disease mice developed phenotypic rear-paw clasping by 16 weeks of age, displayed abnormal rearing behavior, deficits in motor co-ordination and of spatial working memory. Huntington's disease mice with access to running wheels exhibited delayed onset of rear-paw clasping, normalized levels of rearing behavior and amelioration of the cognitive deficits. However, in contrast to our previous environmental enrichment studies, there was no rescue of motor coordination deficits in wheel-running Huntington's disease mice. An abnormal accumulation of brain-derived neurotrophic factor protein in the frontal cortex of Huntington's disease mice was unaffected by running. Striatal and hippocampal brain-derived neurotrophic factor protein levels were unchanged. Brain-derived neurotrophic factor mRNA levels were reduced in the anterior cortex, striatum and hippocampus of Huntington's disease mice, and only striatal deficits were ameliorated by running. Overall, we show that voluntary physical exercise delays the onset of Huntington's disease and the decline in cognitive ability. In addition, our results reveal that some aspects of hippocampal dependent memory are not entirely reliant on sustained hippocampal brain-derived neurotrophic factor expression.