Biological functions are reflected in the natural variation of proteome configurations across individual cells. Single-cell proteomics methods may decode this variation and empower inference of biological mechanisms with minimal assumptions. This promise is beginning to be realized by sensitive and scalable mass spectrometry methods. Specifically, prioritized single-cell mass spectrometry analysis (pSCoPE) allows for consistent and sensitive analysis of thousands of proteins of biological interest, and multiplexed data independent acquisition methods (plexDIA) afford high throughput and data completeness. These methods have allowed us to interpret protein covariation in different biological systems, including primary macrophages and melanoma cells expressing markers for drug-resistance priming. The focus of the talk will be on conceptual analytical innovations and strategies for data acquisition and interpretation that make single-cell protein analysis accessible, robust and highly quantitative.