During vertebrate skeletal development, the appendicular skeleton forms through endochondral ossification, which involves the intricately regulated multistep differentiation of mesenchymal cells. During this process, mesenchymal condensations initially differentiate into chondrocytes. Then chondrocytes in the center further differentiate into hypertrophic chondrocytes. Hypertrophic chondrocytes express a number of osteogenic factors and induce bone formation. Although numerous studies have provided novel insights into the regulation and function of cartilage development, little is known about the intracellular signaling pathways regulating chondrocyte hypertrophy. Recent study revealed that cyclic guanosine monophosphate (cGMP)-dependent protein kinase II (cGKII) coupled the stop of proliferation and the start of hypertrophic differentiation of chondrocytes. Herein, we review the molecular mechanism of regulation of chondrocyte hypertrophy by cGKII and the interaction between cGKII and other signaling pathways.