Ruthenium and osmium-based photosensitizers (PS) are compounds of interest for use in photodynamic therapy (PDT). These PS’s can be activated by light wavelengths in the range of 400-675 nm, which can be selected based on the tumor environment, treatment area, and available light sources. The objective of this study was to explore these PS’s for the treatment of several relatively aggressive cancer cell lines. A human adenocarcinoma cell line (A549) was treated with ruthenium-based compounds at concentrations of 1, 5, or 10 uM, followed by light treatment of 93 J/cm2 at either 532 nm or 630 nm. Similarly, osmium-based compounds were used to treat A549, murine melanoma (B16F10) and squamous cell carcinoma (SCCVII) cell lines at concentrations of 0.05, 1, or 3 uM, followed by light treatment of 93 J/cm2 at 630 nm. Cells survival was assessed 24 hours after PDT treatment using either alamarBlue or MTT cell viability assays. In-vitro MTT viability assays revealed that ruthenium-based compounds activated with 630 nm light showed high SCCVII cell toxicity at 5uM. AlamarBlue assays have shown that ruthenium based compounds activated by 532 nm light show high A549 cell toxicity at 1uM in-vitro. Osmium-based compounds showed optimal PDT-mediated cytotoxicity in SCCVII, A549, and B16F10 cell lines at a concentration of 1uM activated by 630 nm light, while exhibiting minimal dark toxicity. The Ruthenium and Osmium-based compounds are potentially potent PSs against lung, melanoma and squamous cell carcinoma cells, in-vitro.