While the current smartwatches and cellphones can readily track mobility and vital signs, a new generation of wearable devices is rapidly developing to enable users to monitor their health parameters at the molecular level. Within this emerging class of wearables, microneedle‐based transdermal sensors are in a prime position to play a key role in synergizing the significant advantages of dermal interstitial fluid (ISF) as a rich source of clinical indicators and painless skin pricking to allow the collection of real‐time diagnostic information. While initial efforts of microneedle sensing focused on ISF extraction coupled with either on‐chip analysis or off‐chip instrumentation, the latest trend has been oriented toward assembling electrochemical biosensors on the tip of microneedles to allow direct continuous chemical measurements. In this context, significant advances have recently been made in exploiting microneedle‐based devices for real‐time monitoring of various metabolites, electrolytes, and therapeutics and toward the simultaneous multiplexed detection of key chemical markers; yet, there are several grand challenges that still exist. In this review, we outline current progress, recent trends, and new capabilities of microneedle‐empowered sensors, along with the current unmet challenges and a future roadmap toward transforming the latest innovations in the field to commercial products. Microneedle‐based sensors are a rapidly growing class of wearables. Urgent medical needs coupled with the enormous potential of microneedle biosensors are expected to expedite research and commercialization efforts within the next few years toward realizing the ultimate goal of a subskin microlaboratory. This review summarizes the recent progress, latest trends, potential future directions, and the key challenges in this area.