There have been dramatic advances in melanoma therapy in the last 10 years, yet there is still a demand for effective and affordable therapies. To identify novel therapeutic pathways a transcriptome analysis was performed on zebrafish melanoma models representing the different stages of melanoma progression. Transcriptomic differences between pre-malignant and malignant conditions highlighted lipid metabolism as a potential mediator of progression. A mass spectrometry analysis confirmed multiple changes in lipid composition between wild type fish, pre-malignant and advanced melanoma models. To better investigate metabolism a positron emission tomography (PET) technique was developed in zebrafish. Tumours in the zebrafish were successfully scanned with FDG used to detect human tumours. A novel tracer of unconjugated FA was then developed and, consistent with inferences from the transcriptome and mass spectrometry, was shown to be incorporated into tumours. Demonstrating the feasibility of PET in zebrafish now opens the way to systematic use of this organism in tracer development with potential time-saving and cost benefits. One of the most significantly up-regulated genes exclusive to the malignant state encodes lipoprotein lipase (LPL). LPL is involved in the release and uptake of FA from circulating triglyceride. LPL was found to increase the rate of tumour appearance and tumour growth in a zebrafish tumour assay. LPL was expressed in human tumours and expression correlated with progression. Melanoma cell lines expressed LPL and knocking-down LPL resulted in reduced cell numbers. The effect was most dramatic in WM852 cells. A novel role for LPL in autophagy was identified. WM852 cells treated with LPL siRNA showed a stabilisation of p62/SQSTM and induction of LC3B II. Electron microscopy revealed large autolysosomal vacuoles in the cytoplasm. Additionally many cells showed damaged mitochondria with absent cristae. The dependency of cells on LPL seemed to be modified by the co-expression of fatty acid synthase (FASN) required for de novo FA synthesis, as the magnitude of the effect of LPL-knockdown was dependent on the levels of FASN expressed in melanoma cell lines. Moreover, combining LPL and FASN inhibitors synergised to kill cells previously less sensitive to LPL inhibitor. FASN and LPL co-inhibition could provide a unique combinatorial therapeutic strategy.