Distamycin and netropsin analogues have been designed for targeting specific sequences in DNA. Numerous reviews have been centered on the replacement of N-methylpyrrole with heteroaromatic rings in order to induce better fitting to improve the binding efficiency and the introduction of additional interactions for recognition of GC base pairs at the minor groove of DNA. Most of these designed analogs retained the use of carboxamide-bond for interconnecting the heteroaromatic rings. Computer simulations of netropsin and distamycin has pinpointed the advantages of designing isosteres of the carboxamide-bond for amplifying or attenuating particular interactions to DNA, but have been less studied. The key challenges that must be overcome to realize this goal are the development of feasible synthetic methodologies. This review examined in detail for the first time the electronic, structural, and conformational attributes of the various carboxamide isosteres: (i) neutral isostere-alkenyl and alkyl, (ii) hydrogen donating isostere-urea and carbonylurea, and (iii) hydrogen acceptor isosteres-diazene and diketone. In particular, the ability of these isosteres to participate in non-covalent interactions by tuning the shape and hydrogen bonding to the floor of the minor groove is compared with that of the carboxamide bond. We hope this review will encourage the development of a library of modified isosteres of the carboxamide bond which target DNA with excellent sequence specificity, stronger binding affinity and exhibit improved biological properties. Another goal is to develop synthetic methodolgies for the ready synthesis of poly-isosteric bond used in mimicking of the poly-carboxamide bond for DNA minor groove binding agents, the area in which progress has been slow.