Drug testing applications for efficacy and safety testing in vitro with animal and human cells in various tissue-mimic constructs is gaining momentum in the forms of organ-on-chips, micro patterned populations, organoids etc. Most of these constructs face mass transfer and drug access issues that are well-addressed by micro-systems engineering. However, such systems, though allowing precision controls of microenvironment and the associated benefits such as the miniature sample sizes, there are significant challenges on measurements, scalable techniques, consistency, and robustness, and such issues are becoming more severe when complexity increases in multiple cell-type co-culture configurations that are becoming popular. Here we will illustrate a few configurations of increasing complexity of micro-system engineered drug testing platforms to illustrate these challenges and thus stimulate further innovations to address these issues for practical applications in various forms of in vitro drug testing in academia and industry. The examples will range from micropatterned human embryonic stem cell-based developmental toxicity testing platform in testing 35 compounds, to a bile canaliculi-based contraction assay for testing drug against cholestasis, to microfluidics co-cultured system for testing nutraceuticals against cardiovascular diseases, among others.