While asking and answering questions in class can be an anxiety inducing activity for students, it is a common educational tool used in higher education and medical education. Whether a student participates in asking questions in class can be influenced by a variety of factors, particularly pedagogical, psychological, and cultural. This guide outlines the literature to review major concepts of pedagogical, psychological, and cultural factors that influence question-asking, and then explores how to create an inclusive environment to foster success with question-asking in the classroom. Exploring pedagogical influences demonstrates that active learning, founded in constructivist learning methodologies, lays the framework for learners to ask questions in class. Psychological factors include motivation, interest, engagement, academic emotions, and growth mindset, all of which influence an individual’s likelihood of participating in asking questions in an academic setting such as medical school. Cultural considerations must look at the broader culture surrounding question-asking and the culture of the classroom setting itself, as both impact whether learners will ask questions in class. In addition to pedagogy, psychology, and culture, we also explore specific challenges to consider when encouraging participation in class, such as imposter syndrome, and pose them as opportunities for instructors to be proactive and influence a learner’s choice to ask questions in class. Finally, the factors that go into creating an inclusive environment will be discussed to allow educators to create an optimal learning environment for students in higher education and medical education.