Aquaculture is one of the major consumers of fish meal and fish oil. However, the continuous expansion of aquaculture and the decreasing global availability of marine oil and fish meal force the industry to explore alternative and sustainable alimentary sources for fish feeds. To address this issue, the feasibility of combined replacement of fish meal and oil by vegetable ingredients was investigated in gilthead sea bream (Sparus aurata) and dietary effect on growth performance and tissue fatty acid profiles were examined. Four diets with a low level of fish meal inclusion were supplemented with lysine (0.55%) and contained soy lecithin (1%). Added oil was either fish oil (FO diet) or a blend of a vegetable oil mixture (17:58:25 of rapeseed:linseed:palm oils) replacing fish oil at 33, 66 and 100% (33VO, 66VO and VO diets). No detrimental effects on growth performance were found with the partial fish oil replacement (FO compared to 33VO and 66VO diets), but feed intake and growth rates were slightly although significantly reduced in fish fed the VO diet. The VO diet reduced plasma levels and muscle and hepatic expression of insulin-like growth factor-I (IGF-I). The highest concentration of plasma levels of IGF-I was attained in fish fed 33VO diet, whereas intermediate values were found in fish fed FO and 66VO diets. An opposite trend was found for circulating levels of growth hormone (GH), probably as a result of a reduced negative feedback inhibition from circulating IGF-I. In fish fed FO and 66VO diets different growth compensatory mechanisms mediated by IGF-II and GH receptor type II were observed at the local tissue level. Regarding to histological alterations, the replacement strategy did not damage the intestinal epithelium and signs of lipoid liver disease were only found in fish fed the VO diet. Muscle fatty acid profiles of total lipids reflected the diet composition regardless of season. Increased amounts of 18:2n-6, 18:3n-3 and 18:1n-9 in combination with reduced proportions of 20:5n-3 and 22:6n-3, were found with the progressive replacement of fish oil by vegetable oils. However, fatty acid composition of phospholipids was more constant among FO, 33VO and 66VO groups, and only significant changes were found in VO group, probably because this is an essential fatty acids deficient diet. Tissue-specific robustness of fatty acid signatures was analysed in muscle, liver, mesenteric adipose tissue and brain of fish fed FO and 66VO diets. The fatty acid composition of phospholipids showed tissue-specific differences although it remained almost unaltered by the diet effect. Brain showed the greatest robustness to preserve its specific profile being reasonable to assume that a wide range of neural associated functions were preserved. Attempting to restore the fillet fatty acid profile of fish fed 33VO and 66VO to the original optimal fatty acid make-up of fish continuously fed marine oils, FO diet was used as a finishing diet. Changes in the tissue fatty acid profile followed a dilution process and depending specifically on the absolute amount of different fatty acids consumed during complete production cycle. In summary, 66% of fish oil replacement by vegetable oils is possible in diets containing largely plant-based ingredients without adverse effects on gilthead sea bream growth. Even then, other factors must be borne in mind as sensorial quality, food safety, fish health and welfare.