This chapter explores critical issues concerning “partitioning and transmutation” (P&T) of radioactive waste. These issues have been a subject of discourse in recent years, particularly in the context of the disposal and eventual utilization of plutonium and minor actinides for energy production. The fundamental physical feasibility of separating long-lived radioactive substances from nuclear waste (partitioning, P) and converting them into shorter lived, less hazardous isotopes by irradiation in specific reactors (transmutation, T) has been known for decades. The objective of P&T is to potentially mitigate the harmful effects of radioactive waste not by ensuring its safe containment, but by subjecting it to nuclear-physical conversion into shorter lived radioactive substances. This reduction in the radiotoxicity is regarded by some as a significant benefit of this technology, and it is even associated with the prospect of reducing the required isolation period of a repository for heat-generating waste to secular periods of less than 1,000 years. The chapter provides a critical assessment of these potential advantages and updates previous literature by the authors in this regard.