This document summarizes challenges in conducting natural experiments to measure the causal impact of online advertising at scale. It discusses 5 key challenges: 1) the longitudinal nature of online advertising data, 2) user fragmentation across cookies, 3) lack of predetermined study periods, 4) validating causal models, and 5) dealing with billions of events and terabytes of raw data. Overcoming these challenges requires both engineering and modeling approaches. The document provides examples of how to address issues like seasonality, define effect windows, and implement negative control tests when analyzing large-scale online advertising data.