Sustainability assessment (SA) is a complex appraisal method. It is conducted for supporting decision-making and policy in a broad environmental, economic and social context, and transcends a purely technical/scientific evaluation. This paper focusses on the systematisation of knowledge on technical/scientific sustainability evaluation, by addressing critical decision-making elements focussed on by domain experts. We make a distinction between integrated assessment and SA. Our systemic approach outlines how to move from integrated assessment to SA. The fundamental differences involved concern three levels: ontological, methodological and epistemological. We present a novel methodological framework for SA, based on a literature meta-review of multi-scale and multi-purpose appraisal methodologies, models and indicators. SA is essentially a structured procedure encompassing different field-specific analytical methods and models, for specific applications and decision contexts. External inputs to the methodology are "values" considered in the analysis and boundaries defined, including the relevant sustainability framework. Internal methodological elements comprise approach to be adopted (e.g. "what-if" vs. "what-to"), scenario design and analytical models and measurable indicators for an operational analysis. Methods to quantify uncertainty are key ingredients of the assessment framework. The paper highlights the relevance of and policy challenges for SA development, with due attention for applicability in real-world decision contexts.