Trypanosomiasis is a disease caused by unicellular protozoan parasites. Small ruminants succumb to trypanosomiasis in areas of high tsetse fly challenge, resulting in serious economic loss often to farmers in low-input smallholder systems. At present, trypanosomiasis is treated with trypanocidal drugs, but access to these can be limited, and increasing parasite resistance raises questions about their efficacy. The development of trypanotolerance in small ruminant flocks through targeted breeding strategies is considered a sustainable and economical option for controlling African trypanosomiasis. Recently, quantitative trait loci (QTLs) associated with trypanotolerance traits in sheep have been reported. The results of these studies form the basis for more studies to identify QTLs associated with trypanosomiasis resistance, particularly in African livestock species. For example, signatures of positive selection for trypanotolerance have been identified using genome-wide single-nucleotide polymorphism data. However, there are several challenges in performing genetic analyses using data from low-input smallholder systems, including a lack of recorded pedigree and production records and the need for large sample sizes when flock sizes are often fewer than 50 animals. Breeding strategies to improve trypanotolerance should also preserve existing genetic diversity as well as minimize excessive genetic introgression by trypanosusceptible breeds. This review discusses the possibilities of breeding for trypanosome tolerance/resistance in low-input/low-output small ruminant production systems. Potential challenges are outlined, and potential available genetic resources are described as a foundation for future work.