Synthetic lethality is a promising concept for future cancer treatment and using siRNAs as the synthetic lethal drug component allows for also covering the space considered as non-druggable by conventional small molecule drugs. Systemic administration of naked siRNA, however, does not result in sufficient cellular uptake without targeting and siRNAs commonly have a short plasma half-life of less than 10 minutes. As a consequence, nanodevices for siRNA targeting and delivery to cancer cells are under extensive investigation, including, for example, chimeric compounds such as siRNA/antibody or siRNA/aptamer conjugates, or carriers such as liposome/chitosan/micelle spheres. As a first step towards testing of the efficacy of siRNA delivery in vivo via different conjugates and complexes, we aimed at developing a standardized breast cancer model system in mice. In this conception, a reporter gene is used for detection of the primary tumor and metastasis and the efficacy of siRNA delivery is measured by reporter gene-targeting siRNAs and in vivo imaging. The use of a uniform siRNA not affecting cellular processes would allow for standardized assessment of siRNA delivery to cancer cells without interferences via differential knockdown efficacies and the readout can directly be performed by quantitative imaging using a Caliper IVIS system. In one line of experiments, we engineered non-metastatic MCF-7 breast cancer cells to express the luminescent reporter firefly luciferase (Luc2) along with a pro-metastatic microRNA. This produced strongly luminescent tumors upon implantation and ex vivo examination of lungs and liver revealed prominent metastatic spread. In a second line, we engineered MCF-7 cells with a near-Infra Red Fluorescent Protein (iRFP) reporter, lacking the pro-metastatic microRNA. The reporter signal followed the increase of the tumor volume and the mice lacked detectable metastasis formation in the liver and the lungs as assessed by ex vivo imaging. In vitro experiments indicated that iRFP-targeting rather than Luc2-targeting siRNAs were effective in silencing the respective reporter without exerting substantial non-specific toxicity to the cells. Considering this in conjunction with the easier handling of the iRFP reporter than the Luc2 reporter during in vivo imaging, the system with the iRFP reporter might represent a more suitable platform for testing siRNA delivery, so that we presently set up a corresponding metastatic mouse model with this system as well.