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Bioactive secondary metabolites from endophytic fungi provide a robust foundation for novel natural metabolic scaffolds with a plethora of applications. These filamentous fungi contain gene clusters that encode highly significant metabolites; however, many of these clusters remain concealed in laboratory-like settings. Consequently, disparate strategies encompassing genetic manipulation(s) and or metabolomic interventions are obligatory for activating such silent gene clusters and improving metabolite yield. The metabolomic approach basically involves exhaustive exploration and structural information about the cellular metabolome, whereas the genomic approach utilizes complex gene tailoring and refactoring—viz., CRISPR-Cas9—to extract valuable metabolites that are not produced naturally by the indigenous strain. This chapter discusses consolidated utilization of “omics”-based methodologies for sustainable exploitation of bioactive compounds by deploying these ascomycetes.