Tropical theileriosis is a significant tick-borne disease affecting cattle. For decades an empirical live attenuated vaccine has been the primary method of controlling disease. The vaccine is produced through prolonged culture of Theileria annulata schizont-transformed macrophages, but how loss of virulence occurs remains unclear. Notably attenuated (vaccine) macrophages display dampened dissemination potential compared with their original, virulent counterparts. In addition, parasite schizonts in attenuated macrophages have significantly lost their ability to differentiate into merozoites. This review discusses the changes that occur during long-term passage of T. annulata-transformed bovine macrophages and how they contribute to loss of virulence, defined as heightened dissemination. Finally, we also suggest that a common parasite-dependent pathway is potentially involved in both macrophage dissemination and parasite merogony.