We find that the PI3K/Akt pathway is frequently active in T-ALL cells but with very heterogeneous patterns, that pan-PI3K but also γ-specific inhibitors can efficiently suppress biochemical activation of Akt in T-ALL cells, and that combination therapy including PI3K inhibition is a promising direction but requires high-resolution investigations to reveal mechanistic insights in order to bring these treatment strategies into the clinic. Here, PIK3CD is linked to acute lymphoblastic leukemia.