Water is the primary medium through which climate change influences the Earth’s ecosystems and therefore people’s livelihoods and wellbeing. Besides climatic change, current demographic trends, economic development and related land use changes have direct impact on increasing demand for freshwater resources. Taken together, the net effect of these supply and demand changes is affecting the vulnerability of water resources. The concept of ‘vulnerability’ is not straightforward as there is no universally accepted approach for assessing vulnerability. In this study, we review the evolution of approaches to vulnerability assessment related to water resources. From the current practices, we identify research gaps, and approaches to overcome these gaps a generalized assessment framework is developed. A feasibility study is then presented in the context of the Lower Brahmaputra River Basin (LBRB). The results of the feasibility study identify the current main constraints (e.g., lack of institutional coordination) and opportunities (e.g., adaptation) of LBRB. The results of this study can be helpful for innovative research and management initiatives and the described framework can be widely used as a guideline for the vulnerability assessment of water resources systems, particularly in developing countries.