Brown and beige adipocytes produce heat and control systemic energy via non-shivering thermogenesis (NST). Historically, thermogenesis in brown and beige adipocytes was thought to be exclusively through a mitochondria-localized protein, uncoupling protein 1 (UCP1). However, recent studies identified UCP1-independent thermogenic mechanisms in adipocytes. Importantly, UCP1-independent pathways significantly contribute to systemic energy and glucose homeostasis. The finding of UCP1-independent mechanisms provided new opportunities to target the pathways in vivo. In this review, we discuss the current understandings of thermogenic mechanisms in adipocytes with a focus on Ca2+ futile cycling.