Multidrug resistance has emerged as a significant concern with infections caused by Acinetobacter baumannii. Ample evidence supports the involvement of mobile genetic elements in the transfer of antibiotic resistance genes, but the extent of variability and the rate of genetic change associated with the acquisition of antibiotic resistance have not been studied in detail. Whole-genome sequence analysis of six closely related clinical isolates of A. baumannii, including four from the same hospital, revealed extensive divergence of the resistance genotype that correlated with observed differences in antimicrobial susceptibility. Resistance genes associated with insertion sequences, plasmids, and a chromosomal resistance gene island all showed variability. The highly dynamic resistance gene repertoire suggests rapid evolution of drug resistance.