BACKGROUND: In 1997, the pursuit of greater accountability and effectiveness in humanitarian response prompted a multi-stakeholder collaboration to develop a set of indicators and standards to guide humanitarian practitioners, published later in the form of the Sphere Handbook. Twenty years after the first edition of the Handbook was developed, and in order to guide the 2018 revision, an assessment of the evidence base for current Water, Sanitation and Hygiene (WASH), Food Security and Nutrition, and Health Action indicators, as compared to evidence collated by the 2015 LSHTM Humanitarian Health Evidence Review (HHER), was conducted. METHODOLOGY: In order to assess the utility of the Sphere indicators as a tool with which to monitor and evaluate humanitarian activities, indicators from the WASH, Food Security and Nutrition, and Health Action chapters of the Sphere Handbook were analysed and classified according to the SMART criteria. Each indicator was then assessed based on existing evidence related to the effectiveness of humanitarian health interventions as compiled in the HHER. RESULTS: Of the 159 Sphere indicators intended to guide humanitarian response, only 2 met all of the SMART criteria. The remaining 157 did not provide any time indication for the measurement of the indicator. Furthermore, only 11 standards (23%) and 14 indicators (8%) are supported in part by 33 studies identified in the HHER. Less than one third of studies captured by HHER that explore interventions related to WASH, nutrition, or health could be linked to existing Sphere indicators. CONCLUSION: It is not possible to adequately link the 2011 Sphere indicators and standards to their sources in their current constitution, and they are not sufficiently evidence-informed. In the absence of clear measurement definitions, they do not provide necessarily detailed guidance. While recognising that a number of indicators have emerged as a combination of empirical evidence, expert experience, and "common sense", a focus on fewer indicators, each better defined, is likely to enhance the practical application of the Sphere Handbook in humanitarian settings.