A physical examination represents a fundamental step in diagnosing diseases. Due to the role that hormones play in the regulation of numerous biological processes in various organs and systems, endocrine diseases cause a variety of clinical manifestations that can be easily identified with a careful physical examination and can guide the clinician to specific diagnoses. Furthermore, the presence of specific clinical signs in various endocrine-metabolic diseases can predict the risk of developing comorbidities and serious adverse events. In this article, we present some of the main clinical signs of endocrine-metabolic diseases and the risk of comorbidities, summarizing the pathogenetic mechanisms that lead to their formation. The aim is to highlight how the identification of these specific signs can reduce the number of dynamic tests and the costs necessary to reach the diagnosis and allow the early identification of any complications associated with these diseases, improving the clinical management of affected patients.