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Our ability to understand the cellular complexity of tissues has been revolutionized in recent years with significant advances in proteogenomic technologies including those enabling spatial analyses. This has led to numerous consortium efforts, such as the human cell atlas initiative which aims to profile all cells in the human body in healthy and diseased contexts. The availability of such information will subsequently lead to the identification of novel biomarkers of disease and of course therapeutic avenues. However, before such an atlas of any given healthy or diseased tissue can be generated, several factors should be considered including which specific techniques are optimal for the biological question at hand. In this review, we aim to highlight some of the considerations we believe to be important in the experimental design and analysis process, with the goal of helping to navigate the rapidly changing landscape of technologies available., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Immunology.)