The global road network is probably the largest, and still growing, man-made infrastructure. This “giant” generates transformative planetary changes, requiring the allocation of vast amounts of economic resources to mitigate its impacts. However, the part of the budget that is employed to make that network environmentally sustainable remains negligible and practitioners need to implement effective measures to get the most out of limited mitigation budgets. Some studies have already shown that investing in mitigation can be profitable, not only for nature, but also economically (e.g., reduction of the cost of damages suffered from wildlife–vehicle collisions). However, not all mitigation actions are equally cost-effective, and many knowledge gaps remain. Instead of an expensive, a priori and by default mitigation, we suggest that an early-stage field work and subsequent monitoring of road impacts will adequately identify priority areas for mitigation and will improve the effectiveness of the investment. A critical review of the economic costs and effectiveness of mitigation actions could guarantee optimal spending of public budgets. Furthermore, a holistic approach, including the exploration of unexpected cascade effects of the mitigation, could help to better justify that investment to the public. Thus, future research on the cost-effectiveness of road management actions should include side effects beyond those expected for target species.