Phosphoinositide-3 kinase (PI3K) pathway activation contributes to mantle cell lymphoma (MCL) pathogenesis but early phase studies of the PI3K p110δ inhibitor GS-1101 have reported inferior responses in MCL compared to other non-Hodgkin lymphomas. As the relative importance of the class IA PI3K isoforms p110α, p110β and p110δ in MCL is not clear, we studied expression of these isoforms and assessed their contribution to PI3K signaling in this disease. We found that while p110δ was highly expressed in MCL, p110α showed wide variation and expression increased significantly with relapse. Loss of PTEN expression was found in 16% (22/138) of cases, while PIK3CA and PIK3R1 mutations were absent. Although p110δ inhibition was sufficient to block BCR-mediated PI3K activation, combined p110α and p110δ inhibition was necessary to abolish constitutive PI3K activation. In addition, GDC-0941, a predominantly p110α/δ inhibitor was significantly more active compared to GS-1101, against MCL cell lines and primary samples. We found that a high PIK3CA/PIK3CD ratio identified a subset of primary MCLs resistant to GS-1101 and this ratio increased significantly with relapse. These findings support the use of dual p110α/p110δ inhibitors in MCL and suggest a role for p110α in disease progression.