The major cause of death worldwide is infectious diseases and about 10 billion deaths, which represent 25% of all the major causes of death per year were recorded due to the rapidly increasing number of infections in hospitals among compromised and injured patients. Recently, the increasing prevalence of multi-drug resistant bacteria which cause serious healthcare-associated infections in hospitals were reported. The emergence of resistance to aminoglycosides, β lactam antibiotics, and methicillin-resistant Staphylococcus aureus cause serious risk for humans, and infections with resistant bacteria are difficult to treat. Vancomycin was earlier used to overcome the problem of methicillin-resistant S. aureus, but unfortunately, vancomycin-resistant S. aureus had appeared in hospitals. In addition, Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae received increasing attention as a determined as dangerous bacterial pathogens. Occurrence of penicillin-resistant Streptococcus pneumoniae is another resistant bacterium that cause infections in immunocompromised or old patients. As the rate of emergence of resistant isolates increased, the development of novel antibiotics is difficult. Actinomycetes, especially Streptomyces species are still the continuous sources of new products and more than two-thirds of the most used antibiotics are from actinomycetes. Streptomyces had the great biosynthetic ability to form antibiotics that stayed it without potential competition with other microbial genera. This review aimed to discuss the emergence of multidrug-resistant bacteria and their biocontrol with effective antimicrobial agents from rare actinomycetes. In conclusion, the development of novel antibiotics is still the aim of many studies, thus screening of new habitats for novel antibiotics is urgently needed.