The pressing demand for a creative method to effectively model human drug responses in preclinical research has prompted the advancement of organ-on-a-chip (OoC) systems. These problems are not detected during preclinical trials, primarily because of inappropriate screening tools that simulate the sophistication of human tissues and offer rapid, accurate screening readouts. Microfluidics and microfabrication are potent tools for designing many systems with great spatiotemporal accuracy for simulating in vivo microenvironments for delivery, discovery, development, and screening of drugs. This approach may be leveraged to study cell responses to pharmacological and mechanical stimuli in a more biologically effective manner. In this article, we review recent advances in OoC with focus on biomimicry, functionality, and properties, as well as multi-organ platforms, which try to recapitulate combined human physiology's fundamental facets. Eventually, we discuss future directions and limitations that require to be addressed for advancing OoC systems toward clinical translation.