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When the goal is to estimate the probability that a specific form of therapy will have a positive clinical effect, the integration of mechanistic knowledge (concerning \u2018the structure or way of working of the parts in a natural system\u2019) may improve the quality of inference. This is illustrated by analysis of three contemporary approaches to the rehabilitation of lateralized dysfunction affecting people living with stroke: constraint\u2010induced movement therapy; mental practice; and mirror therapy. Damage to \u2018cross\u2010road\u2019 regions of the structural (white matter) brain connectome generates deficits that span multiple domains (motor, language, attention and verbal\/spatial memory). The structural integrity of these regions determines not only the initial functional status, but also the response to therapy. As structural disconnection constrains the recovery of functional capability, \u2018disconnectome\u2019 modelling provides a basis for personalized prognosis and precision rehabilitation. It is now feasible to refer a lesion delineated using a standard clinical scan to a (dis)connectivity atlas derived from the brains of other stroke survivors. As the individual disconnection pattern thus obtained suggests the functional domains most likely be compromised, a therapeutic regimen can be tailored accordingly. Stroke is a complex disorder that burdens individuals with distinct constellations of brain damage. 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