The Italy-Croatia Cross Border Cooperation (CBC) Programme is the financial instrument supporting the cooperation between the two European Member States overlooking the Adriatic Sea. The first call for proposals was launched in 2017, identifying four priority axes of intervention. Subsequently, in 2019, the kick-off of the AdSWiM project “Managed use of treated urban wastewater for the quality of the Adriatic Sea” took place in Udine (IT). Adriatic marine waters are generally classified as good to excellent based on the Bathing Water Directive (2006/7/EC). Nevertheless, issues of low productivity or the lack of nutrients have been often suggested, especially on the Italian side. The project addresses the question of whether wastewater treatment plants (WWTPs) discharging to the sea, after applying appropriate pollution control and management technologies, can modulate the nutrient content of their effluents to support localized depleted areas. This idea is borrowed from one of the motivations that support the reuse of treated wastewater for irrigation, thus leading to the return of nutrients (nitrogen, phosphorus, potassium, etc.) to natural biogeochemical cycles. However, the hypothesis of modulating the nutrient composition of wastewater opens up to several critical aspects, including legislative and technological ones. Being aware of the delicate environmental implications, we have undertaken the project involving WWTPs, research centers, municipalities, and legal experts with the aim of investigating in detail the problems related to wastewater reuse, especially with regard to the content of nutrients. Our experimental approach aimed to evaluate appropriate and possibly new treatment technologies to reduce the microbial load and to implement chemical and microbiological tests on the treated wastewater. Results have shown that it can be tricky to draw decisive conclusions because (i) the wastewater management systems differ between the two sides of the Adriatic sea due to the different levels of technological development of WWTPs; (ii) the Italian and Croatian coasts deeply differ in geographic characteristics (i.e., topography, orography, current circuits, presence of rivers) and anthropogenic pressure (i.e., exploitation levels, population density); (iii) the new treatment technologies to lower bacterial contamination need further efforts to raise their technological level of readiness (TRL) and make them implementable in the existing WWTPs. However, in terms of chemical control methodologies, the proposed sensors and biosensors gave positive results, managing to decrease the detection limits for the measured parameters, and the tested technologies for microbiological monitoring were also effective. In particular, the latter was carried out by using recent molecular biology techniques, capable of resolving the microbiota in treated wastewater, which emerged to be strictly related to the features of the WWTPs.