Microorganisms of millions species exist in every corner of the Earth, and form a dynamic genetic reservoir that are not clearly revealed and categorized due to barrier in current cultivation technology. Their applications in biomedical and environmental aspects are more than satisfactory. However, the situation has drastically changed during the turn of the century because of the rapid development of phylogenetic studies based on rRNA sequencing independent of standard laboratory cultivation. More recently, high throughput sequencing technology which enables direct sequencing of community DNA for metagenomic analyses are making a direct impact on our understanding of microbial diversity, ecology, and secondary metabolism. In this review, we highlight some recent progress and innovation on metagenomic research with an emphasis on natural product drug discovery. The rapid path of accumulating decoded metagenomics would be an efficient guide on direct access to the genomes of numerous non-culturable microorganisms for their genomic diversity and associated chemical prosperity for potential medicinal applications.