Incomplete synthesis and neo-synthesis are two major concepts for cancer-associated alterations of cell surface carbohydrate determinants, formulated by Hakomori and collaborators almost 25 years ago. These concepts are still as relevant and useful as ever for cancer-associated alteration of carbohydrate determinants. Incomplete synthesis of carbohydrate determinants occurs through the epigenetic silencing of glycogenes through DNA methylation and/or histone modification in the early stage cancers. The natural selection of more malignant cancer cells occurs through acquisition of hypoxia resistance by constitutively activated hypoxia inducible factors (HIFs) in the advanced stages of cancers. HIFs induce transcription of several important glycogenes, and lead to neo-synthesis of carbohydrate determinants. For instance, expression of sialyl Lewis A/X is induced by epigenetic silencing of glycogenes in the early stages, and is further accelerated in the advanced stages by hypoxia-induced transcription of several glycogenes. Expression of GM2 ganglioside is induced in cancers by altered glycosyltransferase activities, and its N-glycolyl sialic acid content increases by hypoxia-induced transcription of a sialic acid transporter gene. N-glycolyl GM2 thus reflects two cancer-associated genetic abnormalities in a single determinant, and has high cancer specificity. Every carbohydrate determinant is synthesized through multiple steps, each of which is affected by cancer-associated genetic abnormality. Superiority of carbohydrate determinants as cancer-specific molecules over protein determinants is demonstrated in that a single carbohydrate determinant can reflect multiple cancer-associated genetic abnormalities.