Motivation depends on the ability to evaluate whether potential rewards are worth the effort required to obtain them. Disruptions in this process give rise to debilitating motivational syndromes such as apathy and anhedonia, which are prominent across neurological and psychiatric disorders, including depression and Parkinson's disease. Although mesolimbic dopamine has long been central to theories of effort-based decision-making, converging evidence indicates that motivational drive emerges from the interaction of dopamine with a broader set of neuromodulatory systems. Here, we review animal and human studies examining the neurochemical regulation of physical and cognitive effort, focusing on dopamine alongside adenosine, GABA, serotonin, norepinephrine, acetylcholine, and metabolic signals. Across paradigms, dopamine plays a key role in energising behaviour and promoting willingness to exert effort, but alterations across both dopaminergic and non-dopaminergic systems can bias cost-benefit evaluations even when reward sensitivity is relatively preserved. These findings help explain why motivational deficits often persist despite dopaminergic treatment and why clinically similar syndromes may arise from distinct underlying mechanisms. By integrating behavioural, pharmacological, computational, and neuroimaging evidence, this review highlights effort-based decision-making as a translatable framework for understanding motivational dysfunction. We argue that progress will depend on moving beyond single-transmitter models toward systems-level approaches that distinguish between different motivational profiles. Such an approach has important implications for both research and clinical practice, offering a basis for more targeted interventions to alleviate apathy and anhedonia and improve quality of life.