A therapeutic neuromodulation system, comprising: a plurality of electrical terminals configured for being respectively coupled to a plurality of electrodes implanted within tissue; analog output circuitry configured for delivering therapeutic electrical energy between the plurality of electrical terminals in accordance with a set of modulation parameters that includes a defined current value; a voltage regulator configured for supplying an adjustable compliance voltage to the analog output circuitry; monitoring circuitry configured for measuring an electrical parameter indicative of a change of impedance in the tissue; and control/processing circuitry configured for automatically performing a compliance voltage calibration process at a compliance voltage adjustment interval including: periodically computing an adjusted compliance voltage value as a function of a compliance voltage margin, including: periodically directing the monitoring circuitry to measure the electrical parameter value; determining voltage drops based on the measured electrical parameters; computing a function of at least two of the voltage drops indicative of a rate of impedance change; and adjusting at least one of the compliance voltage adjustment interval and the compliance voltage margin based on the computed function; and directing the voltage regulator to adjust the compliance voltage to the adjusted compliance voltage value. a plurality of electrical terminals configured for being respectively coupled to a plurality of electrodes implanted within tissue; analog output circuitry configured for delivering therapeutic electrical energy between the plurality of electrical terminals in accordance with a set of modulation parameters that includes a defined current value; a voltage regulator configured for supplying an adjustable compliance voltage to the analog output circuitry; monitoring circuitry configured for measuring an electrical parameter indicative of a change of impedance in the tissue; and control/processing circuitry configured for automatically performing a compliance voltage calibration process at a compliance voltage adjustment interval including: periodically computing an adjusted compliance voltage value as a function of a compliance voltage margin, including: periodically directing the monitoring circuitry to measure the electrical parameter value; determining voltage drops based on the measured electrical parameters; computing a function of at least two of the voltage drops indicative of a rate of impedance change; and adjusting at least one of the compliance voltage adjustment interval and the compliance voltage margin based on the computed function; and directing the voltage regulator to adjust the compliance voltage to the adjusted compliance voltage value. periodically computing an adjusted compliance voltage value as a function of a compliance voltage margin, including: periodically directing the monitoring circuitry to measure the electrical parameter value; determining voltage drops based on the measured electrical parameters; computing a function of at least two of the voltage drops indicative of a rate of impedance change; and adjusting at least one of the compliance voltage adjustment interval and the compliance voltage margin based on the computed function; and periodically directing the monitoring circuitry to measure the electrical parameter value; determining voltage drops based on the measured electrical parameters; computing a function of at least two of the voltage drops indicative of a rate of impedance change; and adjusting at least one of the compliance voltage adjustment interval and the compliance voltage margin based on the computed function; and directing the voltage regulator to adjust the compliance voltage to the adjusted compliance voltage value.