For almost 5 decades later since it was first discovered in 1958, efforts continue to be made in the medicinal chemistry of camptothecin (CPT) and its derivatives. Thousands of CPT analogues have been prepared. However, many of the earlier CPT derivatives were either too toxic for clinical use or had very poor pharmacokinetics. Efforts in the last 2 decades were most successful and two derivatives, Irinotecan and topotecan, have been clinically approved by the FDA. This review mainly summarizes the design and synthesis of camptothecin drugs in various stages of preclinical or clinical developments.