The interplay between polyamines and G‐quadruplexes has been largely overlooked in the literature, even though polyamines are ubiquitous metabolites in living cells and G‐quadruplexes are transient regulatory elements, being both of them key regulators of biological processes. Herein, we compile the investigations connecting G‐quadruplexes and biogenic polyamines to understand the biological interplay between them. Moreover, we overview the main works focused on synthetic ligands containing polyamines designed to target G‐quadruplexes, aiming to unravel the structural motifs for designing potent and selective G4 ligands.