Highly pathogenic human coronaviruses (CoV) including SARS‐CoV, MERS‐CoV and SARS‐CoV‐2 have emerged over the past two decades, resulting in infectious disease outbreaks that have greatly affected public health. The CoV surface spike (S) glycoprotein mediates receptor binding and membrane fusion for cell entry, playing critical roles in CoV infection and evolution. The S glycoprotein is also the major target molecule for prophylactic and therapeutic interventions, including neutralizing antibodies and vaccines. In this review, we summarize key studies that have revealed the structural basis of S‐mediated cell entry of SARS‐CoV, MERS‐CoV and SARS‐CoV‐2. Additionally, we discuss the evolution of the S glycoprotein to realize cross‐species transmission from the viewpoint of structural biology. Lastly, we describe the recent progress in developing antibodies, nanobodies and peptide inhibitors that target the SARS‐CoV‐2 S glycoprotein for therapeutic purposes.