Evolution of differential regulatory mechanisms can lead to quite distinct physiological attributes. In the present study, we have identified one such regulatory schema that regulates osa-miR408 and responds differentially in drought-sensitive and -tolerant indica rice varieties. A comparison of the drought stress response in drought-sensitive (Pusa Basmati 1 and IR64) and drought-tolerant (Nagina 22 and Vandana) indica rice varieties revealed that, during drought stress, levels of miR408 transcript decrease significantly in sensitive cultivars, whereas they remain elevated in the tolerant cultivars. The trend is reflected in young seedlings, as well as in flag leaf and spikelets of adult plants (heading stage). Members of the plastocyanin-like protein family targeted by miR408 also show the inverse expression profile and thus accumulate at a lower level in tolerant cultivars during drought. Interestingly, some members of this family are implicated in maintaining the cellular redox state and spikelet fertility in Arabidopsis. An investigation of miR408 loci (including promoter) in all four cultivars did not reveal any significant sequence variation indicating an involvement of the upstream regulatory schema. Indeed, a similar variety-specific stress response was found in the Oryza sativa squamosa promoter-binding-like 9 transcription factor that regulates miR408 expression. We further demonstrate that drought-mediated induction of miR408 in Nagina 22 is regulated by [Ca2+]cyt levels. However, [Ca2+]cyt does not appear to regulate miR408 levels in Pusa Basmati 1, suggesting a variety-specific evolution of regulatory schema in rice.