In this review, we describe how pharmacological inactivation can be used to elucidate the central control of skilled limb movement. Local anesthetics and tetrodotoxin block neuronal cell bodies and passing fibers while gamma-aminobutyric acid (GABA) and muscimol only block cell bodies. Blockade induction time is short (several minutes) for all the agents. Blockade duration produced by local anesthetics and GABA is 15-60 min, while that of tetrodotoxin and muscimol is up to several days. We describe our drug injection system, with an integrated microelectrode and a viewing port for visually monitoring drug flow into the injection cannula. We used glucose metabolism to assess the extent of inactivation. Intracortical lidocaine or muscimol injection produces a central core of maximal hypometabolism (1 mm radius), which could be due to drug spread, surrounded by an extensive region (several millimeters) of reduced hypometabolism, possibly due to reduced synaptic activity of neurons receiving projections from the core region. Drug injection only depresses neuronal activity, which contrasts with cooling, where there can be neuronal hyperexcitability at the periphery of the inactivation site. Our experiments in behaving animals show how pharmacological inactivation is an effective analytical tool for dissecting the differential functional contributions of subcortical and cortical forelimb representations to limb movement control.