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Melanocortin receptors (MCS, MC1–MC5) are GPCRs, activated with different affinities by the melanocortin peptides (?-, ?-, ?-MSH and ACTH). They are widely distributed throughout the body displaying a multitude of actions however their role in reproductive physiology is unclear. Previously, we have shown a reduction of pituitary hormone content and abnormalities in testes morphology in male MC3 null mice. The aim of this study was to characterise MCS expression in the male mouse reproductive axis and to investigate the effects of MCS agonists/antagonists on in vitro testicular testosterone production (TP). MCS expression patterns were determined in mRNAs from hypothalami, pituitaries and testes of Balb/c and C57BL/6 male mice by two-step reverse transcriptase (RT) - quantitative (q) PCR and analysed using qBaseplus. To examine the functions of MCS in gonads, testes of Balb/c and C57BL/6 mice were hemi-sected and incubated with the potent MC3 and, to a lesser extent, MC4 agonist ([D-TRP8]-?2-MSH; 0.3–10 ?g/ml) in the presence or absence of hCG (50 mIU/ml) and/or a MC3/MC4 antagonist and MC1/MC5 agonist (SHU9119; 10 ?g/ml) for 5 h at 35 °C in air. There were no significant differences in the pattern of MCS expression between C57BL/6 and Balb/c. The most abundant MC in the hypothalamus and pituitary appears to be MC3 whilst in the testis it was MC2. TP in C57BL/6 mice is 50% less than in Balb/c: confirming published data that the former mice are hypoandrogenic. Activation of MC3 and MC4 using [D-TRP8]-?2-MSH had no or inhibitory effects on basal TP in Balb/c and C57BL/6, respectively. The same ligand decreased TP in both strains in the presence of hCG. In contrast, SHU9119±hCG increased TP threefold compared to basal levels independently of ligand dose in Balb/c. This study suggests that activation of specific MCS can alter TP however further work is required.