Exhausting exercise is challenging for the organism and in particular the circulation is strained enormously. With increasing intensity and duration of exercise plasma levels of CGRP rise most likely due to a release from the working muscles. Exercise performance correlates better with CGRP plasma levels than with heart rate. The calcitonin receptor-like receptor / receptor activity modifying protein-1 (CLR/RAMP-1) complex forming functional CGRP receptors was found on sympathetic neurons and stimulation of these receptors increases heart rate independent on blood pressure drop. We tested the hypothesis that CGRP supports the circulation during exhausting exercise by increasing cardiac output via stimulation of cardiac sympathetic neurons. Heart rate and blood pressure (using telemetry) as a function of exercise load and maximal oxygen consumption (VO2max) was measured in naive wild type (n-wt) mice, wt mice treated with the CGRP antagonist CGRP(8-37) (2 mmol/kg, wt-ag), mice overexpressing a functional CGRP receptor in sympathetic ganglia (CLR-tg) [Kunz et al., 2007. Am J Physiol 293: H2155-2160] and mice lacking a-CGRP (CGRP- ko) [Lu et al., 1999. Mol Cell Neurosci 14: 99-120]. Due to the different genetic backgrounds of CGRP-ko and CLR-tg mice two n-wt groups were measured. VO2max was 133.3 ±3.9 and 141.2 ±3.2 ml min-1 kg-1 in n-wt mice controls for CGRP-ko and CLR-tg respectively. Treatment of n-wt with CGRP(8-37) reduced significantly VO2max by about 7% which was identical to the drop of VO2max found in CGRP-ko compared to their wt controls. In CLR-tg mice VO2max was about 13% higher than in their wt controls. Whereas the heart rate was not significantly different between the different experimental groups mean arterial blood pressure at the moment of VO2max increased in the following order: CGRP-ko < wt-ag < n-wt < CLR-tg. Our data clearly demonstrate that the level of CGRP signaling modulates maximum exercise capacity.