Many decision support methods and systems in pharmacovigilance are built without explicitly addressing specific challenges that jeopardize their eventual success. We describe two sets of challenges and appropriate strategies to address them. The first are data-related challenges, which include using extensive multi-source data of poor quality, incomplete information integration, and inefficient data visualization. The second are user-related challenges, which encompass users’ overall expectations and their engagement in developing automated solutions. Pharmacovigilance decision support systems will need to rely on advanced methods, such as natural language processing and validated mathematical models, to resolve data-related issues and provide properly contextualized data. However, sophisticated approaches will not provide a complete solution if end-users do not actively participate in their development, which will ensure tools that efficiently complement existing processes without creating unnecessary resistance. Our group has already tackled these issues and applied the proposed strategies in multiple projects.