In the human body, cells in a tissue are exposed to signals derived from their specific extracellular matrix (ECM) cues from architectural structure, mechanical properties and chemical composition (proteins, growth factors). Research on biomaterials, in tissue engineering and regenerative medicine aim to recreate such stimuli with engineered materials in order to induce a specific response of cells at the interface. While traditional biomaterials design has been mostly limited to varying individual cues, increasing interest has arisen on combining several features in recent years in order improve the mimicry of extracellular matrix properties. Tremendous progress in combinatorial surface modification exploiting for example topographical features or variations in mechanics combined with biochemical cues enabled the identification of their key regulatory characteristics on various cell fate decisions. Especially gradients facilitated such research by enabling the investigation of combined continuous changes of different signals. Despite unravelling important synergies for cellular responses, challenges arise in terms of fabrication and characterization of multifunctional engineered materials. This review summarizes recent work on combinatorial surface modifications that aim to control biological responses. Modification and characterization methods for enhanced control over multi-functional material properties are highlighted and discussed. Thereby, this review deepens the understanding and knowledge of biomimetic combinatorial material modification, their challenges but especially their potential.