Mining interspecies interactions remain a challenge due to the complex nature of microbial communities and the need for computational power to handle big data. Our meta-analysis indicates that genetic potential alone does not resolve all issues involving mining of microbial interactions. Nevertheless, it can be used to define the building blocks to infer synergistic interspecies interactions and to limit the search space (i.e., number of species and metabolic reactions) to a manageable size. A reduced search space decreases the number of additional experiments necessary to validate the inferred putative interactions. As validation experiments, we examine how multi-omics and state of the art imaging techniques may further improve our understanding of species interactions’ role in ecosystem processes. Finally, we analyze pros and cons from the current methods to infer microbial interactions from genetic potential and propose a new theoretical framework based on: (i) genomic information of key members of a community; (ii) information of ecosystem processes involved with a specific hypothesis or research question; (iii) the ability to identify putative species’ contributions to ecosystem processes of interest; and, (iv) validation of putative microbial interactions through integration of other data sources.