Multilayer Soft Lithography (MSL) is a robust and mature fabrication technique for the rapid prototyping of microfluidic circuits having thousands of integrated valves. Despite the success and wide application of this method, it is fundamentally a planar fabrication technique which imposes serious design constraints on channel routing, feature density, and fluid handling complexity. We present here methods and related instrumentation to remove these limitations by combining the advantages of MSL processing with laser micromachining using a CO(2) laser ablation system. This system is applied to both the dense integration of layer-layer interconnects and the direct writing of microchannels. Real-time image recognition and computer control allow for robust wafer-scale registration of laser ablation features with moulded channel structures. Ablation rates of up to 8 Hz are achieved with positional accuracy of approximately 20 microm independent of mechanical distortions in the elastomer substrate. We demonstrate these capabilities in the design and fabrication of a production scale multi-laminate micromixer that achieves sub-millisecond mixing of two streams at flow rates up to 1 mL min(-1). The marriage of laser micromachining with MSL-based valve integration allows for high-yield fabrication of topologically complex microfluidic circuits having thousands of layer-layer interconnects and integrated valves.