Keloids are persistent raised scars that are difficult to treat because attempts at removal typically results in recurrence. Keloid fibroblasts are the abnormal cell type responsible for the continuous scar protein deposition in this fibrotic skin disease that involves enhanced TGFβ activity. An effective therapy that can eliminate keloid fibroblasts and promote normal healing is needed. We examined the cellular and molecular differences between keloid and normal skin fibroblasts to identify characteristics that may be targeted for therapy. By limiting serum and/ or glucose availability, we found that keloid fibroblasts are sensitive to glucose levels but not to serum withdrawal. Treatment with 2- deoxyglucose, a preclinical drug that blocks glycolytic metabolism, can reduce keloid fibroblast cell size. However, recovery occurs upon drug removal, indicating a cytostatic effect. To eliminate keloids, it would be necessary to induce cell death in order to disrupt the cycle of continuous fibrosis. Thus, we examined the role of HIF-1, a central transcription factor that regulates both glycolytic metabolism and fibrosis, to determine whether blocking its activity in keloid fibroblasts could yield a cytotoxic outcome. Using a chemical inhibitor against HIF-1, we observed a significant reduction in keloid fibroblast numbers. Although small molecule HIF-1 inhibitors have been under development for anemia and cancer therapy, their role in regulating fibrotic genes has led researchers to consider their potential use in the treatment of lung or kidney fibrosis. Since keloid disease may be considered a form of chronic skin fibrosis, reducing HIF-1 activity could provide a therapeutic strategy for keloid treatment.