Despite the transformation of genomics and genetics, DNA- and RNA-based information provides only a partial view of disease etiology and pathogenesis. This has increased awareness that genetic and gene expression data must be integrated with downstream product activity and cellular metabolite regulation to understand disease processes fully. By simultaneously analyzing the genome, transcriptome, proteome, and metabolome, crucial molecular pathways and novel biomarkers associated with various genetic diseases have been identified using multi-omics approaches. A more comprehensive understanding of the complex interactions between genetic factors (genotype) and disease development (phenotype) has been enabled by these approaches. This chapter describes multi-omics protocols for genetic diseases, emphasizing metabolomics and proteomics approaches.