Significance Inbreeding depression (ID) is the reduction of fitness in offspring of related parents. This phenomenon can be quantified from SNP data through a number of measures of inbreeding. Our study addresses two key questions. How accurate are the different methods to estimate ID? And how and why should investigators choose among the multiple inbreeding measures to detect and quantify ID? Here, we compare the behaviors of ID estimates from three commonly used SNP-based measures of inbreeding and provide both theoretical and empirical arguments to answer these questions. Our work illustrates how to analyze SNP data efficiently to detect and quantify ID, across species and traits.