Antibiotic resistance is increasing faster than the drug industry can develop and market new antibiotics. Medical personnel commonly must deal with the resistant gram-positive pathogens including MRSA and VRE, in addition to the problem gram-negative bacteria, Pseudomonas, Acinetobacter, and ESBL producing strains of Klebsiella and E. coli. Clinicians should be familiar with treatment strategies for these resistant pathogens. Because of the lack of novel agents to treat resistant infections, clinicians must use antibiotics judiciously and appropriately to limit further development of resistance. Early, appropriate cultures of the blood, urine, sputum and suspected source, ideally obtained before antibiotic initiation, allow for future de-escalation of antibiotics, or the decision to discontinue antibiotics.