The central role of phosphatidylinositol 3-kinase (PI3K, p110alpha) signaling in allowing cancer cells to bypass normal growth-limiting controls has led to the development of PI3K(p110alpha) inhibitors. A challenge in targeting PI3K(p110alpha) relates to the diverse actions of the PI3K pathway in numerous cell types. Recent findings in mice deficient in PI3K(p110alpha) activity in the heart, demonstrate the critical role of this pathway in protecting the heart against pathological insults. Mice deficient in PI3K(p110alpha) displayed accelerated heart failure in response to dilated or hypertrophic cardiomyopathy. These results help explain the association of cardiomyopathy in cancer patients given tyrosine kinase inhibitors and raise concerns for the use of PI3K(p110alpha) inhibitors in cancer patients with cardiovascular risk factors. Interestingly, an inhibitor of the mammalian target of rapamycin (a downstream effector of PI3K), did not have adverse effects on the heart. A more complete understanding of the complex arms and interactions of the PI3K pathway will hopefully lead to the development of anti-cancer agents without cardiac complications.