Targeted α-particle therapy offers the potential for more specific tumor cell killing with less damage to surrounding normal tissue than β-emitters because of the combination of short path length (50–80 μm) with the high linear energy transfer (100 keV μm⁻¹) of this emission. These physical properties offer the real possibility of targeted (pre-targeted) α-therapy suitable for the elimination of minimal residual or micrometastatic disease. Targeted and pre-targeted radioimmunotherapy (RIT) using α-emitters such as ²¹²Bi (T_1/2 = 1.01 h) and ²¹²Pb (T_1/2 = 10.6 h) has demonstrated significant utility in both in vitro and in vivo model systems. ²¹²Pb, a promising α-particle emitting source, is the longer-lived parent nuclide of ²¹²Bi, and serves as an in vivo generator of ²¹²Bi. The radionuclide has been successfully used in RIT and pre-targeted RIT and demonstrated an enhanced therapeutic efficacy in combination with chemotherapeutics, such as gemcitabine and paclitaxel. The following perspective addresses the modes of radionuclide production, radiolabelling and chelation chemistry, as well as the application of ²¹²Pb to targeted and pre-targeted radiation therapy.