Amid the recent attention justly focused on the potential problem of microbial sources for weapons of bioterrorism, it is also apparent that human pathogens frequently isolated from infections in patients from community and hospital sources have been growing more resistant to commonly used antibiotics. Much of the growth of multiple-drug-resistant (MDR) bacterial pathogens can be contributed to the overuse of broad-spectrum antimicrobial products. However, an equally troubling and often overlooked component of the problem involves the elegant ways in which pathogenic bacteria continually evolve complex genetic systems for acquiring and regulating an endless array of antibiotic-resistance mechanisms. Efforts to develop new antimicrobials have over the past two decades been woefully behind the rapid evolution of resistance genes developing among both gram-positive and gram-negative pathogens. Several new agents that are best suited for use in the hospital environment have been developed to combat staphylococci resistant to beta-lactam antimicrobials following acquisition of the mecA gene. However, the dramatic spread in the US of the now common community strain of Staphylococcus aureus USA300 has shifted the therapeutic need for new antibiotics useful against MRSA to the community. As the pharmaceutical industry focused on discovering new agents for use against MRSA, hospitals in many parts of the world have seen the emergence of gram-negative pathogens such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae that are clinically resistant to almost all available antimicrobials. Such MDR isolates usually contain multiple-resistance determinants, including loss of outer membrane porins via gene inactivation by chromosomally encoded insertion sequences, up-regulation of inate efflux pumps, as well as acquisition of drug-inactivating enzymes whose genes are encoded on self-transmissible plasmids, integrons, and complex transposable elements. These determinants confer a complex resistance phenotype that is often superimposed on mutations in the primary drug target in the cell. The continued evolution of such a complex array of antibiotic-resistance genes presents a formidable challenge at a time when large pharmaceutical companies have scaled down their presence in the anti-infectives arena.