Several classes of clinically important antibiotics target the bacterial ribosome, where they interfere with microbial protein synthesis. Structural studies of the interaction of antibiotics with the ribosome have revealed that these small molecules recognize predominantly the rRNA components. Over the past two years, three-dimensional structures of ribosome-antibiotic complexes have been determined, providing a detailed picture of the binding sites and mechanism of action of antibacterials, including 'blockbuster' drugs such as the macrolides. Structure-based approaches have come to fruition that comprise the design and crystal structure analysis of novel semi-synthetic antibiotics that target the ribosome decoding site.