The rapid and accurate response of leukocytes to environmental cues is critical for a proper inflammatory reaction to foreign particles or invading microbes. In the last decade, the signal transduction enzyme phosphoinositide 3-kinase γ (PI3Kγ) has emerged as a critical modulator of leukocyte responses, with its effects spanning from recruitment to the site of inflammation to the production of reactive oxygen species. These findings initially obtained from genetically modified mice have led to the development of experimental anti-inflammatory inhibitors with reasonable selectivity and specificity. While such molecules have not yet reached clinical use, preclinical studies combining genetics and pharmacology continue to provide new therapeutic indications for targeting PI3Kγ. Thus, this review focuses on the latest discoveries regarding PI3Kγ function in leukocytes and on the most recent findings in disease models related to immunity.