An inwardly rectifying potassium channel (Kir) is a kind of protein complex that is widely expressed on excitable and nonexcitable cell membranes. Kir channels serve important roles in cellular physiology such as cell excitability and K+ homeostasis. The Kirs (KIR1-7) are regulated by many factors: phosphatidylinosital-4, 5-bisphosphate (PIP2), ATP, or G-proteins. Other factors like polyamines, kinases, pH, and Na+ ions act cooperatively to modulate Kir channels. Different types and specific distributions of KIR channels determine the diversity of regulatory mechanisms. This review provides insight into Kir channel regulation.