Plant programmed cell death (PCD) is an essential process in plant-pathogen interactions. Importantly, PCD can have contrasting effects on the outcome depending on context. For example, plant PCD in plant-biotroph interactions is clearly beneficial to plants, whereas it could be detrimental to plants in plant-necrotroph interactions. Sclerotinia sclerotiorum is an agriculturally and economically important necrotrophic pathogen. Previous studies have shown that S. sclerotiorum secretes oxalic acid (OA) to enhance Sclerotinia virulence by various mechanisms including induction of PCD in plants. A recent study has also shown that reactive oxygen species (ROS) generation correlates with induction of PCD during disease development. These studies focus on links between ROS, oxalate, and PCD, and how they impact S. sclerotiorum disease development. I examined the involvement of ROS in pathogenic development of S. sclerotiorum. I identified and functionally characterized two predicted S. sclerotiorum NADPH oxidases (Nox1 and Nox2) by RNAi. Both nox genes appear to have roles in sclerotial development, while only Nox1-silenced mutants showed reduced virulence. Interestingly, the reduced virulence of the Nox1-silenced mutant correlated with decreased production of OA in the mutant. This observation suggests that regulation of ROS by S. sclerotiorum Nox1 may be linked to OA. The next study details the phenotype of plants inoculated with an S. sclerotiorum oxalate deficient mutant (A2), which showed restricted growth at the infected site. This response resembles the hypersensitive response (HR), and is associated with plant resistance responses including cell wall strengthening, plant oxidative burst, and induction of defensin genes. Conversely, leaves infected with wild type showed unrestricted spreading of cell death and were not associated with these resistant responses. Furthermore, previous work had shown that a Caenorhabditis elegans anti-apoptotic gene (ced-9) conferred resistance to wild type S. sclerotiorum, while this gene had negligible effects on the phenotype of plant leaves inoculated with A2 mutants. These findings suggest that HR-like cell death by A2 and PCD by wild type S. sclerotiorum may be regulated by different pathways. As a whole, these results reveal the importance of ROS, oxalate, and PCD in Sclerotinia disease development as well as the significance of interplay between them. These studies contribute to the understanding of the underlying mechanisms of Sclerotinia disease.