Lake sediment records are underrepresented in comprehensive, quantitative, high-resolution (sub-decadal), multi-proxy climate reconstructions for the past millennium. This is largely a consequence of the difficulty of calibrating biogeochemical lake sediment proxies to meteorological time series (calibration-in-time). Thanks to recent methodological advances, it is now possible. This paper outlines a step-by-step, specifically tailored methodology, with practical suggestions for calibrating and validating biogeochemical proxies from lake sediments to meteorological data. This approach includes: (1) regional climate data; (2) site selection; (3) coring and core selection; (4) core chronology; (5) data acquisition; and (6) data analysis and statistical methods. We present three case studies that used non-varved lake sediments from remote areas in the Central Chilean Andes, where little a priori information was available on the local climate and lakes, or their responses to climate variability. These case studies illustrate the potential value and application of a calibration-in-time approach to non-varved lake sediments for developing quantitative, high-resolution climate reconstructions.