The biosynthetic pathways of the Lewis histo-blood type antigens, Lewis a (Le(a)) and Lewis b (Le(b)), in correlation with ABH antigen synthesis and the synthesis of sialyl Lewis antigens, sialyl Lewis a (sLe(a)) and sialy Lewis x (sLe(x)), known as tumor associated antigens are described based on the recent molecular biological studies. Individuals are divided by their erythrocyte Lewis antigen phenotypes into three types, Le (a+b-) which has Le(a) antigen but not Le(b) antigen, Le (a-b+) which has Leb but not Le(a), and Le (a-b-) having neither Le(a) nor Leb. It was verified that Le (a-b-) individuals are the homozygotes with the nonfunctional Lewis gene (Le gene) which is inactivated by the missense mutations. Two kinds of the inactivated Le gene alleles were found in the Japanese population, and named le1 and le2. Individuals having a Le (a+b-) or a Le (a-b-) -non-secretor phenotype are the mutants who lack the secretor enzyme (Se enzyme) activity. The Se gene encoding the Se enzyme has been recently cloned and analyzed for the mutation resulting in inactivation of the Se enzyme of the non-secretor individuals. Our Se gene mutant analyses on the Japanese population ensured that the Se gene is responsible for synthesis of the Le(b) antigen. Mutant analyses of the other genes, H gene and FucTVI gene, which are also involved in the synthesis of Lewis antigens are described. We recently demonstrated that the sLe(a) antigen is the product of the Lewis gene since all le/le patients, who are determined as the genuine Lewis negative individuals by Le genotyping, did not express any kinds of type 1 chain Lewis antigens (Le(a), Le(b), and sLe(a)) in their digestive organs. It is, therefore, unuseful to measure the CA19-9 titer of the genuine Lewis negative cancer patients.