Adenosine triphosphate (ATP) is a primordial versatile autacoid that changes its role from an intracellular energy saver to a signaling molecule once released to the extracellular milieu. Extracellular ATP and its adenosine metabolite are the main activators of the P2 and P1 purinoceptor families, respectively. Mounting evidence suggests that the ionotropic P2X4 receptor (P2X4R) plays pivotal roles in the regulation of the cardiovascular system, yet further therapeutic advances have been hampered by the lack of selective P2X4R agonists. In this review, we provide the state of the art of the P2X4R activity in the cardiovascular system. We also discuss the role of P2X4R activation in kidney and lungs vis a vis their interplay to control cardiovascular functions and dysfunctions, including putative adverse effects emerging from P2X4R activation. Gathering this information may prompt further development of selective P2X4R agonists and its translation to the clinical practice.