Despite significant advances in understanding and outcomes in various domains of cardiology, the prognosis of infective endocarditis (IE) remains dismal. One of the main reasons may rely on an even more intricate diagnosis since epidemiology has shifted towards an aggressive infection, typically in older patients with the involvement of prosthetic valves and cardiovascular implantable electronic devices with earlier clinical presentation. In this novel setting, it is critical to avoid a delay in diagnosis that may delay subsequent adequate treatment, further complications, and ultimately poor clinical outcomes. Accordingly, based on the available data, we will examine the proper use of first-line echocardiography representing the first-line imaging method in patients with clinical suspicion of IE. We will focus on the following three crucial questions: (1) What is the threshold to start the echocardiographic diagnostic workup in stable patients? (2) Has infective endocarditis become a time-dependent diagnosis, even in stable patients? (3) What is the appropriate use of echocardiography in unstable patients? Finally, we propose a new mindset to improve the echocardiographic diagnostic workflow.