Naturally occurring sialic acids can be O-acetylated at any one of four hydroxyl groups, located at position C-4, -7, -8, and -9. This modification, which is found in nearly all animals expressing sialic acids and certain bacteria, is known to be involved in regulating a variety of biological events. One of the more important processes that appear to be heavily influenced by O-acetylation is cancer development. The present review outlines some of the more recent advances towards understanding the role and regulation of sialic acid O-acetylation in human colorectal cancer, basalioma and melanoma. Even though great strides have been made towards identifying and characterising the biological role of O-acetylated sialic acids, detailed information concerning the transferase activity responsible for this modification remains vague. The 7(9)-O- and 4-O-specific acetyltransferases were identified in bovine and horse submandibular glands, respectively, over 30 years ago, however despite the efforts of a number of groups these enzymes have stubbornly escaped purification and cloning, remaining elusive. Here we will attempt to summarise the available data gathered over several decades, as well as detailing recent advances towards understanding the mechanism and regulation of this enigmatic enzyme.