Marine actinomycetes are prolific sources of marine drug discovery system contributing for several bioactive compounds of biomedical prominence. Metagenomics, a culture-independent technique through its sequence- and function-based screening has led to the discovery and synthesis of numerous biologically significant compounds like polyketide synthase, Non-ribosomal peptide synthetase, antibiotics, and biocatalyst. While metagenomics offers different advantages over conventional sequencing techniques, they also have certain limitations including bias classification, non-availability of quality DNA samples, heterologous expression, and host selection. The assimilation of advanced amplification and screening methods such as φ29 DNA polymerase, Next-Generation Sequencing, Cosmids, and recent bioinformatics tools like automated genome mining, anti-SMASH have shown promising results to overcome these constrains. Consequently, functional genomics and bioinformatics along with synthetic biology will be crucial for the success of the metagenomic approach and indeed for exploring new possibilities among the microbial consortia for the future drug discovery process.