The search for telomerase inhibitors has been widely explored in the last few years, since telomerase activity in somatic cells can be considered as a general cancer mark. One of the possible strategies is the capping of telomere 3'-end (the enzyme substrate) in a conformation not available to the recognition of telomerase, with particular attention to G-quadruplex structures. Small organic molecules, able to induce and/or stabilize G-quadruplexes, have been synthesized and studied in many different research groups. Here, we mean to critically analyze the class of hydrosoluble perylene di-imides (HPDIs), which offers the intriguing possibility to fix the hydrophobic molecule moiety (perylene) able to bind to the terminal G-quartet of telomeric G-quadruplex, while widely varying the number and features of the hydrophilic side chains, which interact with the DNA grooves. We will show that, using the strategy, it is possible to significantly improve HPDIs efficiency in inhibiting telomerase and their selectivity for telomeric G-quadruplex with respect to duplex genomic DNA.