Pannexin1 (Panx1) is a broadly expressed glycoprotein forming heptameric channels in the plasma membrane that allow for the controlled release of ATP from cells. Extracellular ATP is a crucial signaling molecule during inflammation and injury responses, and by stimulating purinergic (P2) receptors it amplifies NLRP3 inflammasome activation, enhances leukocyte infiltration, and provides a positive feedback loop in T lymphocytes, leading to their sustained activation. Extracellular ATP is rapidly converted to adenosine through the action of CD39 and CD73 ectonucleotidases, which dampens inflammation and promotes the resolution of tissue injury. Genetic or pharmacological inhibition of Panx1 channels has been shown to regulate these processes during the initiation and resolution of the inflammatory response. Moreover, by releasing ATP from cells undergoing apoptosis, Panx1 channels provide a “find me” signal for phagocytes to locate and clear these dying cells from injured tissues. Here, we review the current knowledge on the contribution of the Panx1/P2X7/NLRP3 axis to cardiac ischemia/reperfusion injury, a condition that involves accelerated cardiomyocyte death and an excessive inflammatory response, which can lead to heart failure. Similarities with Panx1-mediated signaling during ischemia/reperfusion are examined in other organs like the brain and kidneys. Finally, targeting of Panx1 channels with re-purposed drugs, such as probenecid, carbenoxolone, mefloquine or spironolactone, or with novel specific approaches involving mimetic peptides or mini-antibodies are discussed.