Activation of iNKT cells by CD1d-presented agonists is a potentially potent immunotherapeutic tool. α-galactosylceramide (α-GalCer) is the prototypic agonist but its excessive potency with simultaneous production of pro- and anti-inflammatory cytokines hampers its potential use. New agonists with a modified polar head are recognized by and activate iNKT cells, both in vitro and in vivo. Significantly, direct recognition in vitro does not anticipate in vivo functionality. We published how a weak in vitro agonist, HS44, induces a strong Th1 response in vivo, similar to aGalCer, consequently, inducing an efficient iNKT cell dependent antitumor response in the B16 mouse model. New analogs more similar to a galactose conformation induce an even stronger and more Th1 specific response. One of them induced an absolutely specific Th1 response as judged by the systemic cytokine prolife in serum, with no traces of Th2 cytokines or capacity to induce a Th2 response. The characteristic cytokine storm produced upon α-GalCer administration was not induced, but only Th1 cytokines, which translates in increased antitumor response upon direct administration, both as a preventive and therapeutic treatment, more efficiently controlling the establishment of lung metastases. Secondary transactivation of immune cells is potently induced, with strong mobilization of both adaptive and innate cells. In vivo cytotoxicity experiments show differential efficiency to α-GalCer depending on the susceptibility of target cell to NK lysis. In addition,  in vivo depletion experiments demonstrate the involvement of NK cells and Mø in tumor killing, depending on the target tumor and the agonist. A massive Th1 associated chemoquine production is induced, with some pattern differences that may underline mechanistic differences in the antitumor response between both agonists. Finally, these analogs are also recognized by human iNKT cells, also showing differences in fine specificities with differential recognition of some analogs compared to murine iNKT cells.