Lead is a toxic heavy metal that can cause a range of health problems. In this context, the vascular system is a particular target of the deleterious effects of lead. Lead exerts its toxicity through substitution of other divalent cations such as calcium and zinc, resulting in disruption of homeostasis. Based on the evidence that lead up-regulates endoplasmic reticulum (ER) chaperone glucose-regulated protein 78 (GRP78) and/or antioxidant proteins such as hemeoxygenase-1, it is believed that the heavy metal is able to induce ER and/or oxidative stress in cells. These events also suggest that the unfolded protein response (UPR) system and the antioxidant defense system Kelch-like ECH-associated protein 1-nuclear factor (NF)-E2-related factor 2 (Keap1-Nrf2) play a critical role in adaptive response to lead. In this review, we summarize recent progress in lead toxicity in terms of cellular defense systems, including stress proteins and transcription factors involved in the vascular system.