Proteins are the workhorses of the cell and execute many of their functions by interacting with other proteins forming protein complexes. Multi-protein complexes are an admixture of subunits, change their interaction partners, and modulate their functions and cellular physiology in response to environmental changes. When two species mate, the hybrid offspring are usually inviable or sterile because of large-scale differences in the genetic makeup between the two parents causing incompatible genetic interactions. Such reciprocal-sign epistasis between inter-specific alleles is not limited to incompatible interactions between just one gene pair; and, usually involves multiple genes. Many of these multi-locus incompatibilities show visible defects, only in the presence of all the interactions, making it hard to characterize. Understanding the dynamics of protein-protein interactions (PPIs) leading to multi-protein complexes is better suited to characterize multi-locus incompatibilities, compared to studying them with traditional approaches of genetics and molecular biology. The advances in omics technologies, which includes genomics, transcriptomics, and proteomics can help achieve this end. This is especially relevant when studying non-model organisms. Here, we discuss the recent progress in the understanding of hybrid genetic incompatibility; omics technologies, and how together they have helped in characterizing protein complexes and in turn multi-locus incompatibilities. We also review advances in bioinformatic techniques suitable for this purpose and propose directions for leveraging the knowledge gained from model-organisms to identify genetic incompatibilities in non-model organisms.