Carbon isotope discrimination is a promising trait for indirect screening for improved water use efficiency of C4 crops. In the context of a changing climate, drought is one of the major factors limiting plant growth and yield. Hence, breeding efforts are directed toward improving water use efficiency (WUE) as a key factor in climate resilience and sustainability of crop production. As WUE is a complex trait and its evaluation is rather resource consuming, proxy traits, which are easier to screen and reliably reflect variation in WUE, are needed. In C3 crops, a trait established to be indicative for WUE is the carbon isotopic composition (δ13C) of plant material, which reflects the preferential assimilation of the lighter carbon isotope 12C over 13C during photosynthesis. In C4 crops, carbon fixation is more complex and δ13C thus depends on many more factors than in C3 crops. Recent physiological and genetic studies indicate a correlation between δ13C and WUE also in C4 crops, as well as a colocalization of quantitative trait loci for the two traits. Moreover, significant intraspecific variation as well as a medium to high heritability of δ13C has been shown in some of the main C4 crops, such as maize, sorghum and sugarcane, indicating its potential for indirect selection and breeding. Further research on physiological, genetic and environmental components influencing δ13C is needed to support its application in improving WUE and making C4 crops resilient to climate change.