In this paper a generalized account of relevance as difference-making is developed. It is argued that relevance should not be considered as a particular relation, but as a (higher-order) property of instances of arbitrary relations: namely the property that variations of the relata of the relation instance make a difference for its truth. This generalized account of relevance can be fruitfully applied in many domains, such as (i) logical reasoning with applications to explanation, confirmation, verisimilitude, is-ought inference, (ii) probabilistic reasoning with applications to explanation and confirmation, (iii) nomological and causal implication, (iv) communication, (v) grounding and (vi) essentiality. In conclusion, difference-making relevance is a highly unifying and fruitful philosophical concept.