Spatial transcriptomics methods provide insight into the cellular heterogeneity and spatial architecture of complex, multicellular systems. Combining molecular and spatial information provides important clues to study tissue architecture in development and disease. Here, we present a comprehensive do-it-yourself (DIY) guide to perform such experiments at reduced costs leveraging open-source approaches. This guide spans the entire life cycle of a project, from its initial definition to experimental choices, wet lab approaches, instrumentation, and analysis. As a concrete example, we focus on tertiary lymphoid structures (TLS), which we use to develop typical questions that can be addressed by these approaches.