The WHO recommends ‘testing, tracking and isolation’ of COVID-19 cases as the ‘backbone’ of pandemic response; these seemingly simple recommendations can be daunting for many countries in the Global South. In this commentary based on data from India, we dissect and exemplify some of the underlying vulnerabilities of the countries in the Global South that may impede effective implementation of WHO guidelines from the standpoint of vulnerability assessment and risk management. In the midst of urgent decision-making underlying vulnerabilities can be overlooked, as technical and logistical aspects take precedence. However, differentials in vulnerability can not only modulate the outbreak impact, but also the capacity and effectiveness of the response. Countries need to design their response with due consideration of existing capacity gaps and vulnerabilities to ensure a sustainable response that can avert knee-jerk reactions and minimize likely cascading effects.