Downstream processing of protein products of mammalian cell culture currently accounts for the largest fraction of the total production cost. A major challenge is the removal of host cell proteins, which are cell-derived impurities. Host cell proteins are potentially immunogenic and can compromise product integrity during processing and hold-up steps. There is an increasing body of evidence that the type of host cell proteins present in recombinant protein preparations is a function of cell culture conditions and handling of the harvest cell culture fluid. This, in turn, can affect the performance of downstream purification steps as certain species are difficult to remove and may require bespoke process solutions. Herein, we review recent research on the interplay between upstream process conditions, host cell protein composition and their downstream removal in antibody production processes, identifying opportunities for increasing process understanding and control. We further highlight advances in analytical and computational techniques that can enable the application of quality by design.