The increasing incidence of drug resistance among bacterial pathogens is currently a major threat to human health. Actinomycetes have been recognized as a significant source of pharmaceuticals, especially antibiotics. In the last several decades, a decrease caused by various factors has been observed in the interest towards natural products in the drug discovery process. This is partly stemmed from the use of standard screening methods that result in the rediscovery of the same compounds. Genome mining has become a highly exciting tool for drug discovery since it has unveiled an enormous existence of previously unknown biosynthetic potential in actinomycetes. In particular, metagenomics has been used to uncover antimicrobial compounds and antibiotic resistance genes in uncultured microbial communities in a large number of habitats. So, the detection of resistance can provide an indication of antibiotic production from environmental samples. This brief review aims to provide a new perspective to uncover new antibacterial compounds using antibiotic resistance-based screening.