Hypoxia is a naturally occurring event in solid tumours due to aberrant growth rates, unchecked proliferation and unregulated vascularity. Intratumoural hypoxia has been shown to contribute to malignant progression through the regulation of hypoxia-inducible factors (HIFs), transcription factors that in turn regulate a variety of stem-like and promigratory genes. Several recent meta-analyses of cancer patients administered Non-Steroidal Anti Inflammatory Drugs (NSAIDs) over the long term show a reduction in both pre and post-operative risk ratios (RR) demonstrating that NSAIDs have anti-cancer activity. The main function of NSAIDs is as a pain relieving medication by inhibiting cyclooxygenase (COX). This was originally believed to be the cause for their anti-cancer activity as COX enzymes are known to be upregulated in a variety of cancers. However, several groups have contested this theory with a variety of methods including; using NSAID derivatives that do not inhibit COX, using amounts that are either above or below that required to inhibit COX enzymes, and by studies with COX-2 null animals or cell lines. Given the above observations for the anticancer activity of NSAIDs, it was important to understand more precisely the mechanism(s) through which NSAIDs may act as a cancer treatment. Therefore, 5 NSAIDs and 1 non-COX-2 inhibitory NSAID derivative were examined for their mechanisms of action as anticancer drugs in vitro using murine melanoma and breast cancer cell lines as models.