Insulin resistance is a pathological basis for the development of type 2 diabetes mellitus (T2DM), and has been a key and hot topic for T2DM research recently. Furthermore, an increasing number of reports demonstrate that some sphingolipids play a critical role in regulating insulin signal. For instance, both ceramide and ganglioside monosialo 3 (GM3) can reduce insulin signal sensitivity and lead to insulin resistance. Their mechanisms may be associated with caveolin localization and formation of caveolae on membrane. On the contrary, another remarkable sphingolidid, sphingosine-1-phosphate (S1P), dramatically enhances insulin signal by redox signaling pathway. Both negative and positive effects of sphingolipids on insulin signal imply the involvement of calcium signal. Thus it can be seen that detecting both extracellular calcium influx and intracellular calcium transient in real time may satisfy the speculation of insulin signal regulation with sphingolipids at the ion channel level. Therefore, we will review the mechanisms of modulation of some sphingolipids, including ceramide, GM3 and S1P, on insulin signal. The potential strategies of sphingolipids activity alteration and insulin resistance improvement will be involved in this review as well, which will make great strides in T2DM research.