It is becoming more evident that many aspects of tumour promotion arise from persistent and unresolving inflammation. One of the key molecules mediating the inflammatory processes in tumour promotion is the cytokine, tumour necrosis factor-alpha (TNF-alpha). Clinically, elevated serum concentrations and increased expression of TNF-alpha are present in various pre-neoplastic and malignant diseases, compared with serum and tissue from healthy individuals. Although over the last few decades high-dose administration of TNF-alpha has been used as a cytotoxic agent, recent pre-clinical cancer models have provided critical evidence to support the link between chronic, low level TNF-alpha exposure and the acquisition of pro-malignant phenotype (i.e., increased growth, invasion and metastasis). Furthermore, sophisticated cellular systems are being utilised to dissect the crucial role TNF-alpha plays in the communication of stromal/inflammatory cells and tumour cells. Understanding the intricate roles of TNF-alpha in the process of tumour promotion will assist in the development of novel cancer therapeutics.