TRP proteins, in most cases, provide localized Ca2+ increases for spatially defined signal transduction processes. They are activated by as yet unclear mechanisms, many involving the complex phospholipase C and phosphatidylinositol pathways. In mouse endothelial cells at least seven TRPs are expressed, including TRPC1, TRPC2, TRPC3, TRPC4, TRPC6, TRPV4 and TRPM4. As shown previously, TRPC4 is an indispensable component of agonist-induced Ca2+ entry channels in native endothelial cells which essentially contributes to agonist-induced vessel relaxation and microvascular endothelial permeability, although, it is still open, whether TRPC4 acts as channel-forming subunit and/or essential constituent for channel activation. Utilizing the mouse model is one way to address this question and to provide novel insights for the biological functions of TRPC4. Here we review recent results on heterologously expressed TRPC4 and summarize what is known on the phenotype of the TRPC4-/- mice generated in our laboratory.