Cross-flow filtration is a high throughput method of separating particles (including cells and macromolecules) from fluid and from smaller sized particles. This study has two major purposes: (1) to demonstrate experimentally that lift-based cross-flow techniques allow for sieve-free separations based on size that follow the theoretical predictions and (2) investigate the effects of an alternative sieve-free separation mechanism based on ratcheting of particle trajectories. Through utilizing the shear rates accessible in cross flow filtration along with control of the permeate, feed and retentate fluxes, we can precisely regulate the transmission of particles through membranes with pore sizes about 10 times larger than the particle diameter by utilizing transport processes occurring in the channel. By increasing the shear rate, the transmission of particles through the membrane significantly decreases, and the decrease follows the theoretical predictions for inertial lift based separations. Additionally, adjusting to lower permeate flux allows for less transmission of particles. The trends exhibited for the transmission as a function of parameters such as shear rate, permeate flux, etc. agree with the theoretically predicted trends. The study shows the critical shear rates and permeate fluxes that allow only ~1% of the particles to transmit through the membrane, which optimizes selectivity. Finally, the sieve free separation mechanism based on the ratcheting of particle trajectories is investigated. This mechanism can lead to sieve-free separations of nanoparticles or proteins which are too small to separate based on hydrodynamic lift. Using 1.5 nm and 3.4 nm nano-spheres, we can show that at shear rates that would have no inertial lift effects on the particles, there is some evidence of particle retention and separation. A mechanistic understanding of sieve-free separation of proteins could enable cross-flow separation of product proteins in the bio-pharmaceutical industry, while lift based separations can reduce fouling in waste water recovery.