Motor rehabilitation after hemiparetic stroke is essential to soften physical disability (Furlan, 2014). Nevertheless, current interventions are mostly designed for well recovered individuals and often exclude stroke survivors with rather limited motor ability (Sterr and Conforto, 2012). Given that, and further advancing our research agenda in this arena (Sterr et al., 2002; Sterr and Freivogel, 2003, 2004; Sterr, 2004; Sterr et al., 2006; Sterr and Saunders, 2006), we recently tested the efficacy of a 2-week modified constraint-induced (CI) therapy program in chronic stroke individuals with very low-functioning upper limb hemiparesis (Sterr et al., 2014a). We tested the influence of both the intensity of daily motor training (90 vs. 180 minutes) and the restraint of the less affected upper limb (restraint vs. no restraint) on treatment outcomes. Sixty-five individuals were randomly assigned to four experimental conditions (90 minutes of training with or without restraint, and 180 minutes of training with or without restraint). They were assessed at baseline and after the intervention (2 weeks before, immediately before and after, 6, and 12 months after). Across the cohort, motor function improved significantly, and treatment benefits were largely sustained over the 12 months of follow-up. Analysis of the different treatment variants, however, revealed interesting yet unexpected findings, particularly with regards to the relationship between intensity (amount) of daily training and motor outcomes. As suggested by previous work (Sterr et al., 2002), longer sessions of daily training were expected to yield better outcomes than short sessions, a finding in line with the theory that massed practice is essential for neuroplasticity processes driving the functional improvements induced by CI therapy. However, this was not entirely the case. While we found some differences suggesting greater benefit of longer training sessions, the picture was not as clear as one might expect. This pointed to an interaction between training intensity and motor outcomes in low-functioning chronic stroke that appears to be different from that seen in less severe chronic hemiparesis, where the concept of ‘the more the better’ often holds true (Figure 1). We argued that this intensity-outcome relationship is moderated by variables that highly depend on the level of residual recovery. A key candidate for this moderation is fatigue. Fatigue is identified as rather common, yet obscure problem in stroke survivors (Wu et al., 2015). Post-stroke fatigue is multifactorial and seems to result from a complex interaction among biological, psychosocial, and behavioral factors (Wu et al., 2015). Here, we discuss the role of fatigue in motor rehabilitation of low-functioning chronic stroke using the framework recently suggested by Kluger et al. (2013). Although relatively different from, yet not antithetic to other fatigue models (e.g., Wu et al., 2015), we believe their framework provides conceptual and mechanistic support to our hypothesis. According to that framework, neurological, including post-stroke fatigue encompasses two domains: Perception of fatigue and fatigability. Perception of fatigue refers to a subjective sense of effort or exhaustion, whereas fatigability is related to an objective decline in performance. Although these two types of fatigue might be largely interrelated (e.g., an increased sense of effort would usually contribute to impair performance), they might also act independently and still significantly affect the individual's engagement with activities posing high motor and/or cognitive demands. This is because those two types of fatigue are likely to be caused by different, yet potentially interacting factors. For instance, perception of fatigue could be induced by homeostatic (e.g., metabolic stimuli, such as depletion of energy reserves in skeletal muscle and/or brain tissue) and/or psychological (e.g., decreased motivation) mechanisms, while fatigability could occur due to declines in skeletal muscle force production and/or deficits in task-related neural processing (Kluger et al., 2013). Based on that, we propose that low-functioning chronic stroke survivors are highly susceptible to get into a complex fatigued state, which renders motor training ineffective. This state is more likely to be reached by individuals undergoing longer training sessions. Essentially, we elaborate here on the possibility that a combination of general deconditioning and compromised neural processing might greatly increase both perception of fatigue and fatigability in those individuals, which substantially reduces their engagement with motor training and thereby decreases the likelihood for neuroplasticity processes driving behavioral improvements.