Glutathione (GSH) is the most abundant antioxidant in the cell, and it is responsible for neutralizing reactive oxygen species (ROS). ROS can promote osteoclast differentiation and stimulate bone resorption and are some of the primary drivers of bone loss with aging and loss of sex steroids. Despite this, the role of GSH biosynthesis during osteoclastogenesis remains controversial. Here, we show that the requirements for GSH biosynthesis during osteoclastogenesis in vitro and in vivo are unique. Using a metabolomics approach, we discovered that both oxidative stress and GSH biosynthesis increase during osteoclastogenesis. Inhibiting GSH biosynthesis in vitro via the pharmacological or genetic inhibition of glutamate cysteine ligase (GCLC) prevented osteoclast differentiation. Conversely, the genetic ablation of GCLC in myeloid cells using