This paper proposes a methodology for the parametrization of Ground-Fault Relays (GFRs) in medium-voltage distribution networks with resonant grounding. In these networks, a Petersen coil suppresses the self-distinguishing Phase-to-Ground (Ph-G) faults, whereas permanent Ph-G faults are detected by connecting a low-ohmic grounding resistor in parallel with the Petersen coil, thus enabling the operation of the assigned GFRs. The proposed methodology assures the security of the GFRs by considering the transient response of residual (zero-sequence) currents before the connection of a grounding resistor. Furthermore, safety is assured through the maximum-allowed operating times of the GFRs, given by the dangerous touch and step voltages, which are critical for back-up GFRs during distant Ph-G faults. The selectivity is achieved through timing coordination of the GFRs’ operation, using self-adaptive differential evolution and variable penalties. The proposed optimization model minimizes the pick-up-current settings together with the GFRs’ operating times for metallic and resistive Ph-G faults, thus increasing the sensitivity considerably. For radial network topologies the proposed methodology assures reliable and safe GFR operations for Ph-G faults with a resistance of up to 100 Ω. Moreover, since the dependability of distant in-loop GFRs is questionable, a communication-assisted solution is proposed based on a directional criterion.