Cell polarity, or cell asymmetry is a fundamental property of all metazoan cells. Loss of cell polarity is associated with cancer progression and this loss of cellular organisation represents a hallmark of epithelial cancer. Core polarity complexes have been shown to exert tumour suppressor function in several experimental models and polarity complex members such as Scribble are often lost or mislocalised in human cancer. As Scribble is a large multi-domain scaffold protein, an understanding of how Scribble interacts with its binding partners is important to characterise the mechanisms involved in Scribble's ability to establish and maintain cell polarity as well as to act as a tumour suppressor. Previous studies have demonstrated that the interaction between Scribble and a key binding partner beta-PIX is important in neuronal transmission, directed migration as well as apoptosis. Nonetheless, the exact mechanisms involved are least well understood. This study further characterise this important physical interaction and reports that Scribble PDZ1 and PDZ4 domains are important for this interaction. This study suggests that the nature of Scribble and beta-PIX interaction may be dependent on their specific sub-cellular localisation. Based on the present study, together with published data, three different models describing the regulation of Scribble and beta-PIX interactions are proposed: (1) Trans and (2) Cis steric hindrance of Scribble interferes with beta-PIX binding, (3) Allosteric site/s of Scribble is important in beta-PIX interaction. Together, this study propose new testable models of Scribble and beta- PIX interactions that have biological consequences for our understanding of Scribble's function in cell polarity and tumour suppression.