The discovery of antibiotics was paralleled by the evolution of antibiotic resistance which is probably the best example of contemporary evolution in action. The selection pressure, imposed by indiscriminate use of antibiotics, has changed the scale, mode and tempo of antibiotic resistance evolution. The presence of multidrug resistance, wide range of adaptability features and the infectivity make antibiotic resistance of Shiga toxin-producing Escherichia coli (STEC) more dangerous. The characterization, prevalence and the virulence factors of STEC have been profusely reported, whereas, the antibiotic resistance has been largely ignored because the antibiotic use in STEC infections is controversial. Thus, the current review has focussed on the source, evolution, persistence, mechanism, dissemination and control of antibiotic resistance viz-a-viz the STEC infections. The resistance development occurs by the inactivation of antibiotics, regulating the membrane permeability, modification of natural antibiotic targets or the use of efflux pumps against antibiotics. And, the dissemination of resistance genes occurs vertically by DNA replication and horizontally by conjugation, transduction and transformation. The prevention of development and dissemination of antibiotic resistance needs international public health bodies to rationalize the antibiotic use, prevent the flux of antibiotics into the environment, develop the rapid diagnostics tests, undertake proper surveillance of antibiotic resistance, promote the research on antibiotic resistance prevention, promote the research and development of novel alternative antibiotics, and encourage the widespread social awareness campaigns against the inappropriate antibiotic usage.