Innate immunity is the first-line of non-specific host defense mechanism against pathogens, regardless of the type of strains and mutants. This pivotal component of viral immunology, extremely critical for protecting host cells against infections, has largely been overlooked for SARS-CoV-2 infection. While effective immunization against SARS-CoV-2 reduces the severity of the disease, constantly emerging viral mutants and variant strains continue to pose difficult challenges for effective development of vaccines. This perspective emphasizes the necessity to assess the involvement of the innate cellular immunity against SARS-CoV-2 infection. This most critical aspect of the generic host defense system deserves consideration to broaden the therapeutic scope for effectively mitigating SARS-CoV-2 infection and related pathogenic consequences.