The synthesis of β-lactams, tetracyclines, and erythromycins as three of the major families of antibiotics will be described herein. We will describe why these antibiotics were the ultimate synthetic targets in the past and how modern synthetic organic chemistry has evolved to address these challenges with new, improved strategies and methods. An additional aspect we would like to highlight here is the fact that these first syntheses had to be particularly creative as most of the modern synthetic methods were not available at that time, or were developed in the course of these syntheses.