Lead intoxication was first associated with increased coproporphyrin excretion almost 100 years ago; but not until the 1930's were abnormalities in blood protoporphyrin detected. These later findings have been interpreted as an inhibition by lead of iron incorporation into protoporphyrin during heme synthesis. The testing and application of this hypothesis had to await three more decades of research during which prophyrin/heme biosynthesis was elucidated, control of the pathway was intensively studied, and methodology was greatly improved. The heme biosynthetic pathway is uniquely affected by lead at several sites. These toxic effects can be manifested as increased coproporphyrin and delta-aminolevulinate excretion, decreased erythrocyte delta-aminolaevulinate dehydratase activity, and increased erythrocyte protoporphyrin concentration, all of which have been used and promoted as diagnostic tests for lead intoxication. Among these, the last appears to be becoming the test of choice. The historical background of this development is discussed from a biochemical viewpoint.