Adenocarcinoma of the lung, a leading cause of cancer death, frequently displays mutational activation of the KRAS proto-oncogene but, unlike lung cancers expressing mutated EGFR, ROS1, or ALK, there is no pathway-targeted therapy for patients with KRAS-mutated lung cancer. In preclinical models, expression of oncogenic KRAS^G12D in the lung epithelium of adult mice initiates development of lung adenocarcinoma through activation of downstream signaling pathways. In contrast, mutationally activated BRAF^V600E, a KRAS effector, fails to initiate lung carcinogenesis despite highly efficient induction of benign lung tumorigenesis. To test if phosphoinositide 3-kinase (PI3K)-α (PIK3CA), another KRAS effector, might cooperate with oncogenic BRAF^V600E to promote lung cancer progression, we used mice carrying a conditional allele of Pik3ca that allows conversion of the wild-type catalytic subunit of PIK3CA to mutationally activated PIK3CA^H1047R. Although expression of PIK3CA^H1047R in the lung epithelium, either alone or in combination with PTEN silencing, was without phenotype, concomitant expression of BRAF^V600E and PIK3CA^H1047R led to dramatically decreased tumor latency and increased tumor burden compared with BRAF^V600E alone. Most notably, coexpression of BRAF^V600E and PIK3CA^H1047R elicited lung adenocarcinomas in a manner reminiscent of the effects of KRAS^G12D. These data emphasize a role for PI3K signaling, not in lung tumor initiation per se, but in both the rate of tumor growth and the propensity of benign lung tumors to progress to a malignant phenotype. Finally, biologic and biochemical analysis of BRAF^V600E/PIK3CA^H1047R-expressing mouse lung cancer cells revealed mechanistic clues about cooperative regulation of the cell-division cycle and apoptosis by these oncogenes. Cancer Res; 73(21); 6448–61. ©2013 AACR.