Toxin-antitoxin systems (TAS) are genetic modules controlling different aspects of bacterial physiology. They operate with versatility in an incredibly wide range of mechanisms. New TA modules with unexpected functions are continuously emerging from genome sequencing projects. Their discovery and functional studies have shed light on different characteristics of bacterial metabolism that are now applied to understanding clinically relevant questions and even proposed as antimicrobial treatment. Our main source of knowledge of TA systems derives from Gram-negative bacterial studies, but studies in Gram-positives are becoming more prevalent and provide new insights to TA functional mechanisms. In this review, we present an overview of the present knowledge of TA systems in the clinical pathogen Staphylococcus aureus, their implications in bacterial physiology and discuss relevant aspects that are driving TAS research. "This article is part of a Special Issue entitled: Dynamic gene expression, edited by Prof. Patrick Viollier".