To dissect the tissue‐specific functions of atrial natriuretic peptide (ANP), we recently introduced loxP sites into the murine gene for its receptor, guanylyl cyclase‐A (GC‐A), by homologous recombination (tri‐lox GC‐A). For either smooth‐muscle or cardiomyocyte‐restricted deletion of GC‐A, floxed GC‐A mice were mated to transgenic mice expressing Cre‐recombinase under the control of the smooth‐muscle SM22 or the cardiac αMHC promoter. As shown in these studies, Cre‐mediated recombination of the floxed GC‐A gene fully inactivated GC‐A function in a cell‐restricted manner. In the present study we show that αMHC‐Cre, but not SM22‐Cre, with high frequency generates genomic recombinations of the floxed GC‐A gene segments which were transmitted to the germline. Alleles with partial or complete deletions were readily recovered from the next generation, after segregation of the Cre‐transgene. We took advantage of this strategy to generate a new mouse line with global, systemic deletion of GC‐A. Doppler‐echocardiographic and physiological studies in these mice demonstrate for the first time the tremendous impact of ANP/GC‐A dysfunction on chronic blood volume homeostasis. genesis 39:288–298, 2004. © 2004 Wiley‐Liss, Inc.