Antimicrobial drug resistance rates in Greece are among the highest in Europe. The prevalence of carbapenem-resistant Gram-negative species has increased considerably, including endemic strains in intensive care units. Pandrug-resistant Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa are sporadically reported. Methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus rates are also high in Greek hospitals. Multidrug resistance increases risk of mortality, hospitalization duration and costs, and undermines the medical system. Administrative responses initiated include action plans, monitoring systems, and guidelines. Common terminology among involved parties for defining and grading resistance is required. Multidrug-resistant microorganisms challenge clinical laboratories; uniform recommendations towards detection of resistance mechanisms need to be established. Prospective multicenter outcome studies comparing antibiotic regimens and containment methods are needed. Because new antimicrobials against Gram-negative pathogens are not foreseeable, judicious use of the existing and strict adherence to infection control best practice might restrain resistance spread. Awareness of resistance patterns and organisms prevailing locally by reporting laboratories and treating physicians is important.