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Abstract Background Environmental exposures are related to the risk of some types of cancer, and children are the most vulnerable group of people. This study seeks to present the methodological approaches used in the papers of our group about risk of childhood cancers in the vicinity of pollution sources (industrial and urban sites). A population-based case–control study of incident childhood cancers in Spain and their relationship with residential proximity to industrial and urban areas was designed. Two methodological approaches using mixed multiple unconditional logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) were developed: (a) “near vs. far” analysis, where possible excess risks of cancers in children living near (“near”) versus those living far (“far”) from industrial and urban areas were assessed; and (b) “risk gradient” analysis, where the risk gradient in the vicinity of industries was assessed. For each one of the two approaches, three strategies of analysis were implemented: “joint”, “stratified”, and “individualized” analysis. Incident cases were obtained from the Spanish Registry of Childhood Cancer (between 1996 and 2011). Results Applying this methodology, associations between proximity (≤ 2 km) to specific industrial and urban zones and risk (OR; 95% CI) of leukemias (1.31; 1.04–1.65 for industrial areas, and 1.28; 1.00–1.53 for urban areas), neuroblastoma (2.12; 1.18–3.83 for both industrial and urban areas), and renal (2.02; 1.16–3.52 for industrial areas) and bone (4.02; 1.73–9.34 for urban areas) tumors have been suggested. Conclusions The two methodological approaches were used as a very useful and flexible tool to analyze the excess risk of childhood cancers in the vicinity of industrial and urban areas, which can be extrapolated and generalized to other cancers and chronic diseases, and adapted to other types of pollution sources.