Recent general equilibrium theories in macroeconomics are interpreted from the vantage point of C. S. Peirce’s mathematical, semiotic, and evolutionary cosmology here termed the Peirce Conjecture. The Peirce Conjecture was referenced in Nobel Physicist Eugene Wigner’s (1960) famous essay on the effectiveness of mathematics in the natural sciences. Since general equilibrium theory and its recent macro versions, RBC and DSGE models, may be the most mathematical theories in all of economics, the philosophical issues raised about mathematics and mathematical physics in general are here raised for these mathematical macro theories. Preliminary conclusions seem to point toward an intermediate position where the greatest theories of mathematical economics may not be as effective as those of the sciences but may still be an important intellectual and scientific pursuit in the discipline. Similar to Einstein (1921), who emphasized the difference between formal-axiomatic and “practical” geometry, Peirce would have no doubt been interested in general equilibrium theory as the most advanced mathematical theory in the discipline, but also have emphasized the need for a very mathematical, but “practical” approach to macroeconomics. A semiotic interpretation of mathematical macroeconomics could broaden the audience and conversation about this important area of economic inquiry.