With the increasing antibiotic resistance rate of Campylobacter in foodborn animals which might potentially comprised their effectiveness in human therapy, how to reduce or prevent the emergence of resistant Campylobacter has become more and more important. Understandings of the antibiotic resistant mechanisms will obviously help us to achieve this goal. In this study we tried to determine how CmeABC (for Campylobacter Multi-drug Efflux) pump affects the emergence of Fluoroquinolone (FQ)-resistant isolates. Also, we studied the emergence of erythromycin resistance frequency in Campylobacter. jejuni and Campylobacter. coli under the same in-vitro and in-vivo (in chickens) selection pressures, and the possible genetic mechanism(s) responsible for erythromycin resistance in these species. Our results indicate that inactivation of CmeABC reduced the emergence of FQ-resistant mutants on high antibiotic concentrations while over-expression of CmeABC resulted in an increase in the emergence frequency of FQ-resistant mutants and different types of gyrA mutations together with different levels of CmeABC expression conferred varied levels of resistance to FQ antimicrobials, suggesting that this efflux pump may be targeted to reduce development of FQ-resistance in Campylobacter. Plating of C. jejuni or C. coli culture on MH agar plates with or without erythromycin indicated that both Campyloabcter species had a similar low rate of emergence frequency of erythromycin resistance in vitro. Single or multiple tylosin treatment of experimentally infected 3-day old broiler chickens (2g/gallon in drinking water for 3 days) with macrolide-susceptible C. jejuni or C. coli strains, despite not killing all susceptible cells, did not promote the emergence of tylosin-resistant mutants. Sequencing of 23 S rDNA genes revealed no point mutation in the in vitro-selected mutants, indicating other mechanism(s) responsible for the resistance. CmeABC efflux pump was shown to be associated with both intrinsic and acquired macrolide resistance since inactivation of this pump (via allelic replacement) rendered Campylobacter far more susceptible to erythromycin as compared with the parent strains. Together, these results indicated the complexity of ecology of macrolide resistance in Campylobacter on farms and suggested that other factors besides antibiotic selection pressure may be involved in the emergence of resistance to these important antimicrobials in the animal reservoirs.