Adenosine is a neuromodulator that interacting with four receptors, A1, A2A, A2B and A3, is involved in the regulation of several biological functions in different organs and tissues, including the central nervous system, the cardiovascular system and the airways; many pathophysiological states are associated with changes of adenosine levels. For these reasons pharmaceutical companies and academicians performed intense efforts to obtain agonists, antagonists and allosteric enhancers selective for each adenosine receptor subtypes as potential clinical candidates. In fact, therapeutic modulation of the adenosine system could offer the possibility of a “soft” treatment of different diseases, but, due to the ubiquitous distribution of adenosine and of its receptors, the challenge in therapy development depends from specificity for the different receptor subtypes. Some A1 agonists and antagonists, very potent and selective, reached clinical trials for the treatment of different diseases. A1 agonists are clinical candidates for atrial arrhythmias, angina, type 2 diabetes and in pain management, while A1 antagonists are in study as potassium-sparing diuretics with kidney-protecting properties and in chronic heart diseases. Several reviews, recently published and herein cited, reported in detail the biological and clinical aspects of such molecules. This review focuses on the A1 adenosine receptor (A1AR) ligands, both agonists and antagonists, appeared in the literature in the last few years, together with their potential therapeutic application, pointing the attention on their chemical structures and SAR (Structure Activity Relationship) and also reporting new findings on preclinical or clinical trials of some important A1AR ligands synthesized in the past.