This report addresses the problem formulation step of scientific assessments to support the European Food Safety Authority (EFSA) in the development of guidance. The current report is comprised of a review of published literature on approaches for problem formulation, an environmental scan of two years of scientific assessments published in the EFSA Journal, classification of each publication as to its questions and sub‐questions, and a proposed framework and drafted handbook of recommendations to guide problem formulation. Over 700 EFSA publications were reviewed to identify scientific assessment activities, questions, and sub‐questions. A framework was developed to: 1) translate the mandate into assessment questions; 2) define the sub‐questions of each assessment and their relationship, optionally including a conceptual model; and 3) select the approach to take in designing the methods of the protocol for the assessment. The framework and guidance for problem formulation describe the role of literature scans, question formulation, relationships among sub‐questions, and screening and prioritizing sub‐questions. The report includes proposed cross‐cutting language with a common set of terms to promote understanding and application across diverse EFSA domains. For question formulation, the acronym APRIO was proposed, referring to A(gent), P(athway), R(eceptor), I(ntervention), and O(utput) as variously essential elements of all EFSA questions and sub‐questions.