Entry of HIV-1 into targeted host cells is a highly ordered multistage process involving first-receptor attachment, co-receptor binding, and membrane fusion. In this chapter, I will present an overview of progress on HIV-1 entry inhibitors with a focus on chemokine receptor-based antagonists. This chapter, at first, will describe the working mechanisms of chemokine receptors, HIV-1 co-receptors CCR5 and CXCR4, during the replication procedure. Then, the antagonists-based on different mechanisms will be presented in detail. At last, it will summarize and explain the distinct promising entry inhibitors based on co-receptors-interacting proteins, which is inspired by our current work.