The biomass demand to fuel a growing global bio-based economy is expected to tremendously increase over the next decades, and projections indicate that dedicated biomass crops will satisfy a large portion of it. The establishment of dedicated biomass crops raises huge concerns, as they can subtract land that is required for food production, undermining food security. In this context, perennial biomass crops suitable for cultivation on marginal lands (MALs) raise attraction, as they could supply biomass without competing for land with food supply. While these crops withstand marginal conditions well, their biomass yield and quality do not ensure acceptable economic returns to farmers and cost-effective biomass conversion into bio-based products, claiming genetic improvement. However, this is constrained by the lack of genetic resources for most of these crops. Here we first review the advantages of cultivating novel perennial biomass crops on MALs, highlighting management practices to enhance the environmental and economic sustainability of these agro-systems. Subsequently, we discuss the preeminent breeding targets to improve the yield and quality of the biomass obtainable from these crops, as well as the stability of biomass production under MALs conditions. These targets include crop architecture and phenology, efficiency in the use of resources, lignocellulose composition in relation to bio-based applications, and tolerance to abiotic stresses. For each target trait, we outline optimal ideotypes, discuss the available breeding resources in the context of (orphan) biomass crops, and provide meaningful examples of genetic improvement. Finally, we discuss the available tools to breed novel perennial biomass crops. These comprise conventional breeding methods (recurrent selection and hybridization), molecular techniques to dissect the genetics of complex traits, speed up selection, and perform transgenic modification (genetic mapping, QTL and GWAS analysis, marker-assisted selection, genomic selection, transformation protocols), and novel high-throughput phenotyping platforms. Furthermore, novel tools to transfer genetic knowledge from model to orphan crops (i.e., universal markers) are also conceptualized, with the belief that their development will enhance the efficiency of plant breeding in orphan biomass crops, enabling a sustainable use of MALs for biomass provision.