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Abstract With the current spread of clinically relevant multidrug-resistant (MDR) pathogens, insufficient unearthing of new anti-infectives, and the high cost required for approval of new antimicrobial agents, a strong need for getting these agents via more economic and other alternative routes has emerged. With the discovery of the biosynthetic pathways of various antibiotics pointing out the role of each gene/protein in their antibiotic-producing strains, it became apparent that the biosynthetic gene clusters can be manipulated to produce modified antibiotics. This new approach is known as the combinatorial biosynthesis of new antibiotics which can be employed for obtaining novel derivatives of these valuable antibiotics using genetically modified antibiotic-producing strains (pathway engineering). In this review and based on the available biosynthetic gene clusters of the major aminoglycoside antibiotics (AGAs), the possible alterations or modifications that could be done by co-expression of certain gene(s) previously known to be involved in unique biosynthetic steps have been discussed. In this review defined novel examples of modified AGA using this approach were described and the information provided will act as a platform of researchers to get and develop new antibiotics by the antibiotic-producing bacterial strains such as Streptomyces, Micromonospora,…etc. This way, novel antibiotics with new biological activities could be isolated and used in the treatment of infectious diseases conferring resistance to existing antibiotics.