The crucial role of pituitary GnRH receptors (GnRH-R) in the control of reproductive functions is well established. These receptors are the target of GnRH agonists (through receptor desensitization) and antagonists (through receptor blockade) for the treatment of steroid-dependent pathologies, including hormone-dependent tumors. It has also become increasingly clear that GnRH-R are expressed in cancer tissues, either related (i.e. prostate, breast, endometrial, and ovarian cancers) or unrelated (i.e. melanoma, glioblastoma, lung, and pancreatic cancers) to the reproductive system. In hormone-related tumors, GnRH-R appear to be expressed even when the tumor has escaped steroid dependence (such as castration-resistant prostate cancer). These receptors are coupled to a G(αi)-mediated intracellular signaling pathway. Activation of tumor GnRH-R by means of GnRH agonists elicits a strong antiproliferative, antimetastatic, and antiangiogenic (more recently demonstrated) activity. Interestingly, GnRH antagonists have also been shown to elicit a direct antitumor effect; thus, these compounds behave as antagonists of GnRH-R at the pituitary level and as agonists of the same receptors expressed in tumors. According to the ligand-induced selective-signaling theory, GnRH-R might assume various conformations, endowed with different activities for GnRH analogs and with different intracellular signaling pathways, according to the cell context. Based on these consistent experimental observations, tumor GnRH-R are now considered a very interesting candidate for novel molecular, GnRH analog-based, targeted strategies for the treatment of tumors expressing these receptors. These agents include GnRH agonists and antagonists, GnRH analog-based cytotoxic (i.e. doxorubicin) or nutraceutic (i.e. curcumin) hybrids, and GnRH-R-targeted nanoparticles delivering anticancer compounds.