Gram-positive infections are less commonly encountered in the Indian ICU as compared to Gram-negative infections. Despite several antimicrobial options, they can be challenging to treat. Serious gram-positive infections that can lead to ICU admission can be both community or hospital-acquired. The pathogens include Staph. aureus [both methicillin-sensitive (MSSA) and methicillin-resistant (MRSA)], Streptococcus pyogenes (GAS), Streptococcus pneumoniae (SP), Enterococci, and Clostridium difficile. Less common pathogens include other Coagulase-negative Staphylococci (CONS), Streptococci such as Streptococcus agalactiae/dysgalactiae, Listeria, Clostridia, Nocardia, Actinomyces, etc. In this chapter, we will deal with the common serious gram-positive infections and their treatment.