<p>Bridged heterocycles are highly relevant in medicinal chemistry and drug discovery due to the unique features associated with their three-dimensional configuration that ensures great scaffold complexity. In general, inserting bridged systems into a chemical structure positively influences the pharmacokinetic (PK) profile of leads, reducing lipophilicity and enhancing metabolic stability. Several optimization studies show that bridged systems often promoted a significant improvement of the small molecule–enzyme binding interaction due to conformational changes within the biological target active site. To date, many drugs including bridged cores are available in the market to cure several diseases. Given the broad range of biological activities of naturally occurring and (semi)-synthetic bridgehead heterocycles, here, we have thoroughly reviewed the rational design and the structure–activity relationship (SAR) studies of the most remarkable bridged compounds developed during the past decade, to highlight both the chemical and biological roles of these motifs.</p> Graphical Abstract <p></p>