Although classical mutations in genes such as PIK3CA and PTEN occur at a relatively low frequency in haematological malignancies, activation of PI3K signalling is often detected in these tumours. In some conditions, for example acute myeloid leukaemia (AML), this is due to activating mutations of upstream regulators such as the FLT3 tyrosine kinase or RAS. Primary tumour cells taken from patients with AML, acute lymphoblastic leukaemia, chronic lymphocytic leukaemia and multiple myeloma show varying levels of sensitivity to PI3K and mTOR inhibitors. The challenge now is to conduct high quality trials with novel agents that target these pathways to establish the level of clinical response and to identify those subsets of patients that are more likely to respond.