Abstract Introduction: agricultural production in Brazil has grown in recent decades, and rural workers are exposed to many occupational risks. Epidemiological studies on the topic remain limited, especially regarding methodological complexity. Objectives: to present the main methodological challenges to carrying out occupational epidemiological studies in rural areas. Methods: the considerations presented in this article are based on the literature and on the experience of the authors as researchers of this thematic. Results: we approached concepts about target population, living and working place, workers classification, and agricultural production context characterization. We discussed sampling strategies, characterization of economic indicators, including agricultural production and mechanization level, pesticide exposure, such as chemical types, forms, and frequency of exposure, pesticide poisonings, and availability and use of personal protective equipment. We described the necessary care with biological samples and aspects involving interviewers, training, field work, and clinical and logistical issues. Conclusion: despite the methodological and logistical challenges, adequate planning enables successful research studies, of great complexity and high scientific level, about the health-work relationship in agricultural activity.