The phosphoinositide 3-kinase (PI3K) pathway is one of the major signalling pathways in the cell and is involved in regulating many important cellular functions including growth, proliferation, metabolism, and survival. Somatic genomic alterations that result in aberrant activation of this pathway are frequently found in many human tumours including gastrointestinal cancers. The most common PI3K pathway mutations detected in gastrointestinal cancers are single base changes in PIK3CA, the gene that codes for the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K). Mutations in the PIK3CA gene are detected in up to 20% of all colorectal tumours. Mutations have also been detected in a number of other PI3K pathway genes including PTEN, a negative regulator of the PI3K pathway, and PIK3R1, the regulatory subunit of PI3K. Studies expressing mutated PIK3CA in cells support the conclusion that these mutations are both activating and oncogenic. In addition, PIK3CA mutations have been found to confer resistance to some therapies, while recent reports suggest that mutation of PIK3CA is associated with poor prognosis for patients with colorectal cancers. As a result, there is now considerable clinical interest in the PI3K pathway, both as a potential therapeutic target (with numerous pharmaceutical companies now developing and trialling inhibitors that target PI3K and/or the PI3K pathway) and as a potential marker for targeting individualised anticancer treatments.