Different RNA interference (RNAi) techniques, such as small interfering RNA and shRNA (short hairpin RNA), have been widely used in genomic and transcriptomic research to confirm the biological effects of natural products on specific targets. These methods, referred to as “reverse genetics,” are invaluable for deciphering the function of genes and identifying new targets in a phenotype-based manner. High-throughput RNAi assays are frequently utilized to identify small-molecule sensitizers and inhibitors, as well as essential genes and synthetic lethal genes. The suppression of targeted genes can help elucidate key mechanisms and pathways implicated in the natural compounds’ activities by weakening cellular responses to a targeted molecule of interest (Hirota et al., 2012; Yin and Kassner, 2016; Chen et al., 2020). Through multiplex sequencing screening of pooled and barcoded shRNA libraries, the importance of ATP1A1 in regulating cellular sensitivity to aurilide B (a marine natural product) was revealed (Takase et al., 2017). However, differences in the mRNA levels may not necessarily reflect concomitant alterations in the protein expression and activity , potentially leading to false positives and off-tar get effects (Sachse et al., 2005; Marine et al., 2012). T o address this issue, promising techniques for the discovery and iden­tification of target research have been provided by the development of the CRISPR-Cas9 genome editing technology (Hsu et al., 2014; Knight et al., 2018). DrugT argetSeqR utilizes high-throughput sequencing, CRISPR-Cas9, and computational mutation discovery-based genome editing to present a novel approach for identifying targets of small bioactive molecules. The application of this approach led to the identification of kinesin-5 as the target of the synthetic anticancer agent called “ispinesib” and “dihydroorotate dehydro­genase,” which was identified as a possible target for the treatment of acute myeloid leukemia. Furthermore, the natural product “isobavachalcone” which is derived from the plant used in traditional Chinese medicine (TCM) called Psoralea corylifolia and inhibits the activation of an enzyme called dihydroorotate dehydrogenase, which was validated by using techniques such as thermal shift assay, nuclear magnetic resonance (NMR), isothermal titration calorimetry experiments, following a CRISPR screening (Kasap et al., 2014; Wu et al., 2018). In summary, genomics and transcriptomics are powerful tools that have greatly contributed to the discovery and characterization of natural products with therapeutic potential. The integration of these approaches has led to significant advances in the domain of discovering drugs from natural sources.