Folate is a polar (negatively charged) molecule and does not passively diffuse across cell membranes, except at high concentrations. Therefore, folate requires a transporter to facilitate movement through the cell membrane. Two important folate transporters in humans include (1) high-affinity, low-capacity FR; this receptor is not currently a drug target, but may perhaps be someday as it is overexpressed in certain tumors; PMX has similar affinity to folic acid for these receptors, (2) low-affinity, high-capacity RFC that are predominantly used by DHF, THF, MTX, PMX, and PTX; PMX has roughly twice the affinity for RFC compared to MTX. DHF, dihydrofolate; MTX, methotrexate; PMX, pemetrexed; PTX, paclitaxel; THF, tetrahydrofolate.