Aims: The recently sequenced Burkholderia mesoacidophila (previously Pseudomonas mesoacidophila) is a soil organism and as such will be exposed to multiple concurrent stresses in the natural environment. The combinatorial stress potentially experienced by microbes in soil has not been investigated in detail. Methods and Results: The impact of combinatorial stress on growth was investigated using tripartite variables—temperature, nutritional environment and either osmotic or oxidative stress. In nutritionally stringent conditions, increasing diamide concentration had no effect on growth while increasing H2O2 concentration reduced both growth rate and maximum density. Metabolomic studies with oxidative stress revealed specific (unidentified) metabolites associated with diamide tolerance, and an overwhelming dominance of sugars and sugar alcohols in nutritionally stringent conditions with and without the additional stressor. Conclusions: Combinatorial stress tolerance is complex. Temperature had the greatest independent impact on growth, while the impact of the nutritional environment played a key role in oxidative stress tolerance. In nutritionally stringent conditions, the metabolome suggested different tolerance mechanisms for different types of oxidative stress. Significance and Impact of the Study: This work demonstrates the specificity of the stress response, and the need to consider multiple environmental factors to meaningfully investigate tolerance. Both environmental and clinical settings subject bacteria to combinatorial stress and this should be considered in the design of further studies.