Allele-specific gene silencing by RNA interference (RNAi) appears to be a therapeutically useful technique to suppress the expression of disease-causing allele specifically without affecting the expression of corresponding normal alleles. Establishment of such atypical RNAi may provide us a radical treatment without side-effects for various human disorders caused by dominant disease genes. In this study, we show a disease-causing allele-specific RNAi treatment against Huntington’s disease (HD) and non-small cell lung cancer (NSCLC) in vitro and in vivo. In addition to allele-specific RNAi, we also demonstrate another type of atypical RNAi for normalization (fine-tuning) of over-expressed wild type alpha synuclein gene (SNCA) leading to Parkinson’s disease (PD). These atypical RNAi techniques described here may be a potential treatment as a therapy with few side-effects, and may be applicable to treatment of dominantly inherited diseases and possibly also sporadic disorders caused by over-expression of wild-type genes.