The unintended loss of skeletal muscle mass is common in a number of disease states (e.g. cancer, AIDS, sepsis or following bedrest) and can have debilitating consequences for the patient, often leading to a reduced quality of life and a protracted recovery period. Furthermore, muscle acts as an important reservoir of proteins, which are relied upon during periods of disease to provide substrates for hepatic gluconeogenesis and acute phase protein production. Therefore, in the clinical setting it is important to adopt measures that will maintain muscle mass, aiding the recovery process and improving overall outcome. In a bid to prevent or reverse the loss of muscle mass observed in cachectic-inducing conditions it is first necessary to understand the mechanisms responsible for the loss of muscle protein content. Enhanced ubiquitin proteasome-mediated proteolysis of skeletal muscle proteins occurs across a number of diverse atrophying conditions. Proteins are targeted for degradation by the action of a triplet of enzymes, with target specificity provided by the ubiquitin ligase family of proteins of which several hundred members exist. In 2001, two muscle-specific ubiquitin ligases termed MuRF1 and MAFbx (the latter also known as atrogin-1) were identified (Bodine et al. 2001) and appeared transcriptionally upregulated in a number of muscle atrophy models (Lecker et al. 2004). Moreover, animals with a knockout for either the MuRF1 or MAFbx gene were found to be partially resistant to the effects of denervation-induced muscle loss (Bodine et al. 2001). Together, these findings have led researchers to consider MAFbx and MuRF1 as instrumental to the loss of muscle mass in a number of atrophy states and represent the central component of the muscle ’atrophy program’ (Lecker et al. 2004). Elevated in the vast majority of conditions where muscle atrophy is prevalent, the necessity of MAFbx and MuRF1 activity for muscle atrophy to occur remains to be demonstrated in vivo in all but a few conditions. Indeed, while unlikely, the assumed elevation of MAFbx and MuRF1 mRNA levels culminating in a decline in muscle mass may merely be the result of guilt by association. Furthermore, with both ubiquitin ligases under the control of the FOXO transcription factors (Stitt et al. 2004) and often reported as upregulated in concert, their actions as part of the ‘atrophy program’ often appear linked. Significant strides in addressing these pre-conceived notions are provided in this issue of The Journal of Physiology by Baehr et al. (2011). Utilising a glucocorticoid model of muscle atrophy and separate cohorts of MAFbx and MuRF1 knockout mice, the authors demonstrate a clear discord between the role of MAFbx and MuRF1 in the loss of muscle mass following dexamethasone administration. Specifically, 14 days of 3 mg kg−1 dexamethasone treatment significantly decreased muscle mass in wild-type animals, but the catabolic effects of the synthetic glucocorticoid were reduced in MuRF1−/− animals. In stark contrast, MAFbx null mice were afforded no protection from the catabolic effects of the dexmethasone treatment. While examples can be found in the literature where catabolic conditions have not led to elevated expression of MAFbx or MuRF1 mRNA in skeletal muscle, the studies in question are generally constrained by the limited time-points examined, leading to the possibility of any transient changes being missed. The findings by Baehr and colleagues represent a shift in our understanding, demonstrating that MAFbx does not represent a component of the ‘atrophy program’ in all atrophy states. This is not to suggest that MAFbx does not play a role in muscle atrophy per se; previous work from the same group has robustly demonstrated the requirement of MAFbx in the loss of muscle mass following denervation. However, in light of such findings, the notion of a conserved muscle ‘atrophy program’ across diverse muscle atrophy states which includes MAFbx needs refinement. At the dose of dexamethasone examined, the authors noted a decline in the fractional protein synthetic rate of the triceps surae complex in wild-type but not MuRF1 null animals. Coupled with the lack of effect of the dexamethasone treatment in the MuRF1−/− animals on parameters associated with increased proteolysis, it would appear that a major component for the sparing of muscle mass following dexamethasone treatment in MuRF1 knockout animals was the ability to maintain rates of muscle protein synthesis. This observation is particularly intriguing, as it had largely been assumed that MuRF1 was important in reducing muscle protein content by inducing proteolysis of muscle proteins, including myofibrillar proteins. From the work presented by Baehr and colleagues, it would appear apparent that MuRF1's role may extend to one of regulating muscle protein synthesis. Such observations help rationalise the existence of the debate regarding the individual contribution of muscle protein synthesis and protein breakdown in various muscle atrophy conditions (Rennie et al. 2010) and open up new important avenues for investigation. In summary, the results by Baehr et al. (2011) raise interesting questions about our understanding of the muscle-specific ubiquitin ligases and their involvement in muscle atrophy. On the back of their findings it would appear that the roles of both MuRF1 and MAFbx are not as straight-forward as first assumed and that a critical re-examination of the function of both ubiquitin ligases is judicious.