Frizzleds (FZDs) are a family of GPCRs controlling key events in all branches of the developmental Wnt signaling pathway. In this capacity these receptors are mostly active prenatally and have only a limited set of functions in the human adult. Numerous cancer types and subtypes were shown to be dependent on aberrant Wnt signaling and FZDs in particular. Taken together with their GPCR properties, this makes them an attractive drug target for the development of highly specific and efficient targeted therapies against cancer. Despite that, there are few chemical or other agents described targeting FZDs, and an even smaller number bears any clinical relevance. This sparsity dictates the necessity for broader efforts in order to advance in the Wnt pathway-targeting drug discovery. The current work describes the concepts and methodology of an inexpensive high-throughput screening followed by the pipeline of secondary assays in order to identify anti-FZD agents, which will efficiently deactivate Wnt signaling in cancer cells. Specifically, we describe a process and criteria for the selection, generation and statistical validation of a stable cancer cell line based on the well-described luciferase readout (TopFlash) which is then converted into a disease-representative high-throughput-ready screening system. We also provide information on the follow-up test sequence and the post-screening criteria to select FZD-targeting compounds among the hits and to validate them as such. We expect that use of this pipeline will boost the research on clinically valuable Wnt-targeting anti-cancer compounds.