Both complex disorders and monogenetic diseases are often modulated in their phenotype by further genetic, epigenetic or extrinsic factors. This gives rise to extensive phenotypic variability and potentially protection from disease manifestations, known as incomplete penetrance. Approaches including whole transcriptome, exome, genome, methylome or proteome analyses of highly discordant phenotypes in a few individuals harboring mutations at the same locus can help to identify these modifiers. This review describes the complexity of modifying factors of one of the most frequent autosomal recessively inherited disorders in humans, spinal muscular atrophy (SMA). We will outline how this knowledge contributes to understanding of the regulatory networks and molecular pathology of SMA and how this knowledge will influence future approaches to therapies. Copyright © 2013 Elsevier Ltd. All rights reserved.