While pesticide use is subject to strict regulatory oversight worldwide, it remains a main concern for environmental protection, including biodiversity conservation. This is partly due to the current regulatory approach that relies on separate assessments for each single pesticide, crop use, and non-target organism group at local scales. Such assessments tend to overlook the combined effects of overall pesticide usage at larger spatial scales. Integrative landscape-based approaches are emerging, enabling the consideration of agricultural management, the environmental characteristics, and the combined effects of pesticides applied in a same or in different crops within an area. These developments offer the opportunity to deliver informative risk predictions relevant for different decision contexts including their connection to larger spatial scales and to combine environmental risks of pesticides, with those from other environmental stressors. We discuss the needs, challenges, opportunities and available tools for implementing landscape-based approaches for prospective and retrospective pesticide Environmental Risk Assessments (ERA). A set of “building blocks” that emerged from the discussions have been integrated into a conceptual framework. The framework includes elements to facilitate its implementation, in particular: flexibility to address the needs of relevant users and stakeholders; means to address the inherent complexity of environmental systems; connections to make use of and integrate data derived from monitoring programs; and options for validation and approaches to facilitate future use in a regulatory context. The conceptual model can be applied to existing ERA methodologies, facilitating its comparability, and highlighting interoperability drivers at landscape level. The benefits of landscape-based pesticide ERA extend beyond regulation. Linking and validating risk predictions with relevant environmental impacts under a solid science-based approach will support the setting of protection goals and the formulation of sustainable agricultural strategies. Moreover, landscape ERA offers a communication tool on realistic pesticide impacts in a multistressors environment for stakeholders and citizens.