There is currently considerable interest in understanding how the biosynthetic pathways of highly unsaturated fatty acids (HUFA) are regulated in fish. The aim is to know if it is possible to replace fish oils (FO), rich in HUFA, by vegetable oils (VO), poor in HUFA and rich in their 18 carbon fatty acid precursors, in the feed of cultured fish species of commercial importance. Thus many studies have focussed on delta-6 desaturase (Delta 6D) since it is the rate-limiting enzyme involved in HUFA biosynthesis from precursors. The aims of this paper were (i) to review and compare the structure, function, and tissue distribution of the Delta 6D gene in teleosts and (ii) to review the effect of nutrition and environment on the modulation of Delta 6D gene expression and on the activity of this enzyme in teleosts. Most existing studies have clearly shown that Delta 6D is modulated by nutrition and environment in freshwater fish. This modulation allows the control of lipid metabolism and the maintenance of cell membrane functionality. Delta 6D gene expression and enzymatic activity were higher in fish fed VO diets than in those fed FO diets, irrespective of their life cycle in seawater or freshwater; this concurs with expectations regarding the compensation for HUFA deficiency in VO. However, the magnitude of these increases was not great enough to maintain HUFA tissue content. Such a decrease in tissue content may result either from competition between substrates for Delta 6D or from the inhibition of subsequent steps in HUFA biosynthesis, such as elongation or delta-5 desaturation activity. Other studies showed that Delta 6D enzyme activity is stimulated at low temperatures and low salinities, which keep cell membranes fluid. In salmonids, Delta 6D would then play an important role in the adaptation to salinity changes at parr-smolt transformation. In marine fish, similar nutritional and environmental modulations may occur, although conflicting data exist. A low expression of the Delta 6D gene or the involvement of genetic, environmental, or hormonal factors could explain why Delta 6D appears to be barely functional in marine fish. This review shows that, despite the large number of studies investigating the regulation of Delta 6D, little is known about the molecular mechanisms involved. Furthermore, the nutritional and environmental regulation of other enzymes involved in HUFA biosynthesis still need to be investigated to obtain a better understanding of the regulation of HUFA biosynthetic pathways in teleosts, ultimately leading to improvements in fish production.