Widespread development of antimicrobial resistance by major bacterial pathogens including Staphylococcus aureus, Streptococcus pneumoniae, Enterococci, and gram-negative bacilli have emerged as a global healthcare concern. Antimicrobial resistance was first identified during the 1940s and 50s with penicillin resistance in S. aureus. During the 1970s and 80s, methicillin-resistant S. aureus (MRSA) rapidly emerged as a major nosocomial pathogen in hospitals throughout the world. In the 1990s, a variation of MRSA emerged as community-associated MRSA (CA-MRSA), which is contracted outside of the hospital setting, and has become one of the most common pathogens associated with skin and skin structure infections in the United States and other parts of the world. Vancomycin-intermediate S. aureus (VISA) was first reported in 1996, and high-level vancomycin-resistant S. aureus (VRSA) was reported in 2002. S. pneumoniae has demonstrated a significant increase in resistance to macrolides and beta-lactam agents since 1980s, particularly in Asian countries while penicillin resistance is not prevalent among non-meningeal isolates according to the new breakpoints from CLSI. Vancomycin resistant enterococci, particularly E. faecium, is a major concern associated with nosocomial infections in many hospitals. Given the widespread emergence and spread of antimicrobial resistant gram-positive cocci during recent decades, the problem is likely to continue to increase as a critical, clinical problem.