Ecosystem and landscape studies are often faced with less than ideal, large-scale scenarios which are challenged by traditional approaches to experimental design and analysis, primarily because these studies can not be adequately replicated and are confronted by multiple spatial and temporal scales of variation. Variations in parameter and response time further complicate experimental design and data analysis. Rather than struggle with controlling or minimizing the influence of spatial and temporal variation via statistically required replication, we employed BACI and BACIPS designs and applied multiple spatial-scale controls and unbalanced temporal sampling schemes to account for the spatial and temporal structure of the studied system. This multiple-scale design allowed us to assess both pulsed and sustained responses of critical ecosystem processes to a prescribed fire in a nutrient-enriched wetland. A series of regression approaches and confidence intervals were employed to estimate onset, duration, and magnitude of post-fire ecosystem responses. This chapter describes a powerful approach for studying ecosystem disturbance including issue identification, experimental design, data analysis and interpretation, and management recommendations.