The coronavirus disease 2019 (COVID‐19) pandemic can hardly end with the emergence of different variants over time. In the past 2 years, several variants of severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), such as the Delta and Omicron variants, have emerged with higher transmissibility, immune evasion and drug resistance, leading to higher morbidity and mortality in the population. The prevalent variants of concern (VOCs) share several mutations on the spike that can affect virus characteristics, including transmissibility, antigenicity, and immune evasion. Increasing evidence has demonstrated that the neutralization capacity of sera from COVID‐19 convalescent or vaccinated individuals is decreased against SARS‐CoV‐2 variants. Moreover, the vaccine effectiveness of current COVID‐19 vaccines against SARS‐CoV‐2 VOCs is not as high as that against wild‐type SARS‐CoV‐2. Therefore, more attention might be paid to how the mutations impact vaccine effectiveness. In this review, we summarized the current studies on the mutations of the SARS‐CoV‐2 spike, particularly of the receptor binding domain, to elaborate on how the mutations impact the infectivity, transmissibility and immune evasion of the virus. The effects of mutations in the SARS‐CoV‐2 spike on the current therapeutics were highlighted, and potential strategies for future vaccine development were suggested.