Mutant propagation (outgrowth) is an important step in all large-scale gene essentiality experiments, profoundly influencing essentiality assignment produced. Using a simplified mathematical model of competitive outgrowth in a diverse mutant population, we have identified several technological factors (duration of outgrowth, sensitivity of the scoring technique, initial cell titer of each mutant in the population) that have the largest impact on the outcome of the essentiality screen. The model can be used for planning a large-scale gene essentiality screen as well as for analyzing its results, including meaningful comparisons of "essential" gene lists generated by different techniques.