CD1d-restricted natural killer T (NKT) cells have at least two subsets: type I, semi-invariant TCRα chain-expressing (Vα14Jα18 in mice, Vα24Jα18 in humans), and type II, variable TCRα chain-expressing. The protective role of NKT cells in tumor immunosurveillance and immunity has been well documented but paradoxically, there are also studies ascribing a suppressive role to these cells. Recent studies have resolved this paradox by revealing distinct roles for the two types of NKT cells, whereby type I NKT cells enhance anti-tumor responses and type II NKT cells suppress these responses. The finding of cross-regulation between the two types of NKT cells suggests a new immunoregulatory axis. Consideration of the cross-talk of NKT cells along with the well-defined suppression by regulatory T cells could provide new insights into cancer immunotherapy.