The concept that the amino‐terminal segment plays a role in conferring high basal activity to protein kinase CK2 α subunit has been validated by generating two mutants (Y26F and Δ2–6) which are defective both in catalytic activity and in thermal stability. The additional finding that the activity of the two mutants is fully restored upon association with the regulatory β subunit, in conjunction with the observation that synthetic peptides reproducing the N‐terminal segment (1–30) and the activation loop (175–201) of CK2α counteract the functional effects of the C‐terminal domain of the β subunit, is consistent with a mechanism of activation of CK2 where the N‐terminal domain of α and the C‐terminal domain of β play interchangeable roles.