Reversibly switchable proteins are powerful tools with which to explore protein function in vitro and in vivo. For example, the activity of many proteins fused to the hormone-binding domain of the modified oestrogen receptor (ER(TAM)) can be regulated by provision or removal of 4-hydroxytamoxifen (4-OHT). Despite the widespread use of ER(TAM) fusions in vivo, inadequate data are available as to the most efficacious routes for systemic tamoxifen delivery. In this study, we have used two well-characterized ER(TAM) fusion proteins, both reversibly activated by 4-OHT, to compare the effectiveness and kinetics of 4-OHT delivery in mice in vivo by either tamoxifen in food or by intraperitoneal injection. Our data indicate that dietary tamoxifen offers an effective, facile and ethically preferable means for long-term activation of ER(TAM) fusion proteins in vivo.