The past two decades have witnessed a disturbing increase in antimicrobial resistance. Bacterial isolates that are resistant to all currently available antimicrobial agents are emerging. Bacteria with this phenotype are designated multidrug-resistant (MDR) or pan-drug resistant (PDR) strains. What is the genetic basis of this remarkable survival skill? Are advantageous changes in the genome always random? Is antibiotic pressure the cause of growing resistance rates, or does it merely serve as a trigger that selects the archived defense armamentarium within bacteria? In this chapter, we will explore these concepts and discuss: (1) genetic diversity and mutations as its basis; and (2) hypermutators and the mechanisms responsible for high mutation rates. Our chapter will conclude with examples of specifi c point mutations in bacterial enzymes that confer resistance to certain antibiotic classes.