Phosphoinositide (PI) 3-kinases are essential regulators of cellular proliferation, survival, metabolism, and motility that are frequently dysregulated in human disease. The design of inhibitors to target the PI 3-kinase/mTOR pathway is a major area of investigation by both academic laboratories and the pharmaceutical industry. This review focuses on the Class IA PI 3-kinase p110β, which plays a unique role in thrombogenesis and in the growth of tumors with deletion or loss-of-function mutation of the Phosphatase and Tensin Homolog (PTEN) lipid phosphatase. Several p110β-selective inhibitors that target the ATP-binding site in the kinase domain have been identified. However, recent discoveries regarding the regulatory mechanisms that control p110β activity suggest alternative strategies by which to disrupt signaling by this PI 3-kinase isoform. This review summarizes the current status of p110β-specific inhibitors and discusses how these new insights into p110 regulation might be used to devise novel pharmacological inhibitors.