The generation of singlet oxygen (O-1(2)) has been established as the principal mechanism of photodynamic therapy (PDT). Various dyes, metal nanoparticles, and clusters have been shown to sensitize O-1(2). However, metal nano clusters are even more promising candidates as photo sensitizers for this purpose. By understanding the optical properties that lead to efficient O-1(2) generation, one can fully realize their potential as PDT photosensitizers. Three different metal nanoclusters, Au-25, Ag-32, and Au-144, are investigated for their O-1(2) generation efficiency. The Au-144 showed a O-1(2) generation rate that is 2 orders of magnitude higher than that for Au-25 and Ag-32, and several orders of magnitude higher than nanoparticles (> 5 nm) due to Au-144's high absorption cross section-to-volume ratio. The effectiveness of PDT in live cells with nanoclusters was demonstrated by two-photon excitation compared to one-photon excitation. The implication of these results points toward new efficient two-photon O-1(2) sensitizers for photodynamic therapy.