Experience-dependent modulation of neurodegenerative diseases may occur via a wide range of lifestyle factors and environmental exposures. This chapter discusses the pre-clinical models of environmental modulation leading to clinical trials and to the potential findings of new therapeutic targets. Beneficial environmental modulation, such as environmental enrichment, has been shown to improve cognitive and motor functions in a wide range of neurological disorders, including Huntington’s disease (HD), Alzheimer’s disease, Parkinson’s disease, schizophrenia and autism spectrum disorder. Although all these disorders have distinct etiologies, enrichment and exercise have shown behavioural positive effects through different molecular mechanisms, as reviewed elsewhere. Motor impairment caused by certain neurodegenerative diseases such as HD reduces considerably the amount of exercise, which needs to be taken into account. While most studies focus on finding new treatments based on pathological molecular/cellular mechanisms, another interesting approach is to enhance the effect of positive environmental modulation by mimicking the molecular mechanisms of experience-dependent plasticity.