<p>The automatic synthesis of radiopharmaceuticals has a long history, from [¹⁸F]FDG to the most recent metallic radioisotope-labeled radiopharmaceuticals. Initially, the development of the automatic synthesis process focused on radioisotope labeling and high yields, as well as other chemical processes such as HPLC purification. The initial focus of the development of the [¹⁸F]FDG synthesis automatic chemistry module was to prevent radiation exposure and to develop a reproducible process. The synthesis procedure and purification methods were continuously developed to reduce preparation time and simplify purification, for example by using solid-phase extraction, to achieve high radiochemical yields and purity. Recently, there have been automatic chemistry modules optimized for metallic radioisotope labeling, and these machines have demonstrated very high radiochemical yields and short synthesis times. Compared with previous developments, the recent automatic preparation process includes simple chemical synthesis to satisfy GMP regulations because all radiopharmaceutical processes are trackable and reproducible. In this review paper, we describe the development process for each radioisotope labeling for radiopharmaceuticals, as well as the regulatory aspects that satisfy recent GMP regulations.</p>