Osteoarthritis (OA) is the most common joint disease, and in recent years has become a major public health problem. The hallmark of OA is cartilage destruction with local commitment of subchondral bone and the synovial membrane. Hypoxia-inducible factors (HIFs) are transcriptional factors and key regulators of the cellular response to hypoxia. To date, three members of the human HIF-α protein family have been described: HIF-1α, HIF-2α, and HIF-3α. HIF-1α plays an essential role in the articular cartilage (a hypoxic tissue), as it has a protective effect in the maintenance of the articular cartilage matrix, HIF-2α has a harmful effect on the articular cartilage matrix, and HIF-3α acts as a negative regulator of HIF-1α and HIF-2α. Due to the recent growing interest in the role of HIFs in rheumatic diseases, we focused this review on the potential role of these key regulators in articular cartilage maintenance as the central axis in OA development.