The molecular mechanisms underlying the pathogenesis of the malignant Hodgkin's/Reed–Sternberg (HRS) cells of Hodgkin's lymphoma (HL) are largely unknown. This study investigates the contribution of phosphatidyl‐inositide 3 kinase (PI3‐kinase) and demonstrates that Akt, a substrate of PI3‐kinase, is constitutively activated in HL‐derived cell lines. Several downstream effectors of Akt signalling, including glycogen synthase kinase 3 (GSK‐3) α and β and mTOR substrates 4E‐BP1 and p70 S6 kinase, were also phosphorylated in HL cells. The mTOR inhibitor, rapamycin, inhibited phosphorylation of these proteins. Furthermore, LY294002 inhibited phosphorylation of p70 S6 kinase and 4E‐BP1, suggesting that the phosphorylation of p70 S6 kinase and 4E‐BP1 in HL cells is PI3‐kinase dependent. Importantly, HRS cells of primary tumour samples not only expressed high levels of activated Akt but also displayed phosphorylation of downstream targets of Akt activation including GSK‐3, 4E‐BP1, and p70 S6 Kinase. Inhibition of PI3‐kinase and mTOR showed only modest effects on cell survival at the lower serum concentrations. However, rapamycin and doxorubicin acted synergistically to reduce HL cell survival. A combination of rapamycin and chemotherapy should be investigated in the treatment of HL. Copyright © 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.