BACKGROUND Despite the various strategies undertaken in the clinical practice, the mortality rate due to antibiotic-resistant microbes has been markedly increasing worldwide. In addition to multidrug-resistant (MDR) microbes, the "ESKAPE" bacteria are also emerging. Of course, the infection caused by ESKAPE cannot be treated even with lethal doses of antibiotics. Now, the drug resistance is also more prevalent in antiviral, anticancer, antimalarial and antifungal chemotherapies. METHODS To date, in the literature, the quantum of research reported on the discovery strategies for new antibiotics is remarkable but the milestone is still far away. Considering the need of the updated strategies and drug discovery approaches in the area of drug resistance among researchers, in this communication, we consolidated the insights pertaining to new drug development against drug-resistant microbes. It includes drug discovery void, gene paradox, transposon mutagenesis, vitamin biosynthesis inhibition, use of non-conventional media, host model, target through quorum sensing, genomic-chemical network, synthetic viability to targets, chemical versus biological space, combinational approach, photosensitization, antimicrobial peptides and transcriptome profiling. Furthermore, we optimally briefed about antievolution drugs, nanotheranostics and antimicrobial adjuvants and then followed by twelve selected new feasible drug targets for new drug design against drug resistance. Finally, we have also tabulated the chemical structures of potent molecules against antimicrobial resistance. CONCLUSIONS It is highly recommended to execute the anti-drug resistance research as integrated approach where both molecular and genetic research needs to be as integrative objective of drug discovery. This is time to accelerate new drug discovery research with advanced genetic approaches instead of conventional blind screening.