Viral-based gene therapy for neurological diseases provides a daunting challenge. Many neurological diseases, especially neurodegenerative conditions, have unknown etiologies and current viral platforms are largely inadequate for human therapy. The challenges appear surmountable through systematic definition and solution. This review highlights three problem areas for gene therapy; genomic integration, immunogenic responses and regulated gene expression, as well as current progress in those areas. Successful neurological gene therapy will require efficacy along with clear biosafety. Different vector platforms manifest characteristic properties that affect their suitability for human gene therapy and among these are their propensity to integrate, elicit immune responses and enable regulated gene expression.