An account of work on the biosynthesis of secondary metabolites up to 1965 is presented. The earliest suggestions for three of the four major pathways were speculative; for the isoprene rule, hypotheses date to 1877, for the polyketide rule to 1907, and for a role for amino acids in alkaloid biosynthesis to 1910. The fourth major pathway based on intermediates of the shikimic acid pathway has a much shorter history because shikimic acid itself was only identified as a primary metabolite in 1951. In addition to speculation, biomimetic syntheses were carried out in which chemists attempted to duplicate possible biosynthetic pathways in vitro. The classic example was Robinson's synthesis of tropinone in 1917. Direct examination of secondary metabolite biosynthesis was possible with the use of the isotopic tracer technique. This methodology, applied extensively to primary metabolism beginning in 1935 and to secondary metabolism from about 1950, was facilitated by the increasing availability of the 14C isotope. With the use of isotopes as tracers, the broad outlines of secondary metabolite biosynthesis, reviewed here, were established in the period 1950 to 1965.